Publications by authors named "Erik De Clercq"

737 Publications

Exploiting the hydrophobic channel of the NNIBP: Discovery of novel diarylpyrimidines as HIV-1 NNRTIs against wild-type and K103N mutant viruses.

Bioorg Med Chem 2021 May 28;42:116239. Epub 2021 May 28.

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012 Jinan, Shandong, PR China; China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, 44 West Culture Road, 250012 Jinan, Shandong, PR China. Electronic address:

To further explore the chemical space surrounding the "hydrophobic channel" of the NNRTI binding pocket (NNIBP), a new series of diarylpyrimidines (DAPYs) were designed and synthesized as potent HIV-1 non-nucleoside RT inhibitors (NNRTIs). The target compounds were evaluated for anti-HIV potency in MT-4 cells. Most of the synthesized DAPYs exhibited moderate to excellent activity against the HIV-1 wild-type (WT) strain with EC values ranging from 16 nM to 0.722 µM. Interestingly, few compounds displayed remarkable activity in inhibiting K103N mutant virus with EC values ranging from 39 nM to 1.708 µM. Notably, FS2 (EC = 16 nM, EC = 39 nM, SI = 294) was identified as the most significant compound, which was considerably more potent than nevirapine, lamivudine, and comparable to zidovudine. Additionally, the HIV-1 RT inhibition assay confirmed their binding target. Preliminary structure-activity relationships (SARs) and molecular modeling studies were also performed, providing significant suggestions for further optimization.
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http://dx.doi.org/10.1016/j.bmc.2021.116239DOI Listing
May 2021

Design, synthesis and anti-HIV evaluation of novel 5-substituted diarylpyrimidine derivatives as potent HIV-1 NNRTIs.

Bioorg Med Chem 2021 Jun 5;40:116195. Epub 2021 May 5.

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Ji'nan 250012, China; China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, 44 West Culture Road, 250012 Jinan, Shandong, PR China. Electronic address:

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are widely used in combination therapies against HIV-1. As a continuation of our efforts to discover and develop "me-better" drugs of DAPYs, novel diarylpyrimidine derivatives were designed, synthesized and evaluated for their anti-HIV activities in MT-4 cells. All the compounds demonstrated strong inhibition activity against wide-type HIV-1 strain (III) with EC values in the range of 2.5 nM ~ 0.93 μM. Among them, compounds IVB-5-4 and IVB-5-8 were the most potent ones which showed anti-HIV-1 activity much superior than that of Nevirapine, comparable to Efavirenz and Etravirine. What's more, some compounds also showed low nanomole activity against some mutant strains such as K103N and E138K. The selected compound IVB-5-4 was also evaluated for the activity against reverse transcriptase (RT), and exhibited submicromolar IC values indicating that this series compounds are specific RT inhibitors. Preliminary structure-activity relationships and modeling studies of these new analogues provide valuable avenues for future molecular optimization.
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http://dx.doi.org/10.1016/j.bmc.2021.116195DOI Listing
June 2021

Genetic Diversity of SARS-CoV-2 over a One-Year Period of the COVID-19 Pandemic: A Global Perspective.

Biomedicines 2021 Apr 11;9(4). Epub 2021 Apr 11.

Hunan Provincial Key Laboratory of Clinical Epidemiology, Xiangya School of Public Health, Central South University, Changsha 410078, China.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a global pandemic of coronavirus disease in 2019 (COVID-19). Genome surveillance is a key method to track the spread of SARS-CoV-2 variants. Genetic diversity and evolution of SARS-CoV-2 were analyzed based on 260,673 whole-genome sequences, which were sampled from 62 countries between 24 December 2019 and 12 January 2021. We found that amino acid (AA) substitutions were observed in all SARS-CoV-2 proteins, and the top six proteins with the highest substitution rates were ORF10, nucleocapsid, ORF3a, spike glycoprotein, RNA-dependent RNA polymerase, and ORF8. Among 25,629 amino acid substitutions at 8484 polymorphic sites across the coding region of the SARS-CoV-2 genome, the D614G (93.88%) variant in spike and the P323L (93.74%) variant in RNA-dependent RNA polymerase were the dominant variants on six continents. As of January 2021, the genomic sequences of SARS-CoV-2 could be divided into at least 12 different clades. Distributions of SARS-CoV-2 clades were featured with temporal and geographical dynamics on six continents. Overall, this large-scale analysis provides a detailed mapping of SARS-CoV-2 variants in different geographic areas at different time points, highlighting the importance of evaluating highly prevalent variants in the development of SARS-CoV-2 antiviral drugs and vaccines.
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http://dx.doi.org/10.3390/biomedicines9040412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069977PMC
April 2021

Chemical space exploration of novel naphthyl-carboxamide-diarylpyrimidine derivatives with potent anti-HIV-1 activity.

Bioorg Chem 2021 Jun 20;111:104905. Epub 2021 Apr 20.

Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, People's Republic of China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, People's Republic of China. Electronic address:

Fifteen naphthyl-carboxamide-DAPYs were generated to explore chemical space in reverse transcriptase (RT) binding site via lead optimization strategy. They displayed up to single-digit nanomolar activity against wild-type (WT) and rilpivirine-associated resistant mutant E138K viruses, as well as potent inhibitory ability toward the RT enzyme. Compound a1 showed exceptionally inhibitory effects with an EC value of 3.7 nM against HIV-1 wt strain, and an EC of 11 nM targeting mutant E138K. The structure-activity relationships (SARs) of the newly obtained DAPYs were also investigated. Molecular docking analysis elucidated the biological activity and offered a structural insight for follow-up research.
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http://dx.doi.org/10.1016/j.bioorg.2021.104905DOI Listing
June 2021

Hydrophobic Pocket Occupation Design of Difluoro-Biphenyl-Diarylpyrimidines as Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors: from -Alkylation to Methyl Hopping on the Pyrimidine Ring.

J Med Chem 2021 04 14;64(8):5067-5081. Epub 2021 Apr 14.

Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.

Considering the nonideal metabolic stability of the difluoro-biphenyl-diarylpyrimidine lead compound , a series of novel alkylated difluoro-biphenyl-diarylpyrimidines were designed and synthesized based on their structure. Introducing alkyl or substituted alkyl groups on the linker region to block the potential metabolic sensitive sites generated 22 derivatives. Among them, compound with an -methyl group displayed excellent anti-HIV-1 activity and selectivity. The methyl group was hopped to the central pyrimidine to occupy the small linker region and maintain the water-mediated hydrogen bond observed in the binding of compound with RT. The resulting compound exhibited an improved anti-HIV-1 activity, much lower cytotoxicity, and nanomolar activity toward multiple mutants. In addition, has a better stability in human liver microsomes than . Moreover, no apparent in vivo acute toxicity was observed in -treated female, especially pregnant mice. This series of alkylated compounds with highly potency and safety represent a promising lead template for future discovery.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00128DOI Listing
April 2021

2,4,5-Trisubstituted Pyrimidines as Potent HIV-1 NNRTIs: Rational Design, Synthesis, Activity Evaluation, and Crystallographic Studies.

J Med Chem 2021 04 18;64(7):4239-4256. Epub 2021 Mar 18.

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, Jinan 250012, Shandong, PR China.

There is an urgent unmet medical need for novel human immunodeficiency virus type 1 (HIV-1) inhibitors that are effective against a variety of NNRTI-resistance mutations. We report our research efforts aimed at discovering a novel chemotype of anti-HIV-1 agents with improved potency against a variety of NNRTI-resistance mutations in this paper. Structural modifications of the lead led to the identification of a potent inhibitor . yielded highly potent anti-HIV-1 activities and improved resistance profiles compared with the approved drug etravirine. The co-crystal structure revealed the key role of the water networks surrounding the NNIBP for binding and for resilience against resistance mutations, while suggesting further extension of toward the NNRTI-adjacent site as a lead development strategy. Furthermore, demonstrated favorable pharmacokinetic and safety properties, suggesting the potential of as a promising anti-HIV-1 drug candidate.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00268DOI Listing
April 2021

Medicinal chemistry strategies for discovering antivirals effective against drug-resistant viruses.

Chem Soc Rev 2021 Apr 17;50(7):4514-4540. Epub 2021 Feb 17.

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan, 250012, Shandong Province, P. R. China.

During the last forty years we have witnessed impressive advances in the field of antiviral drug discovery culminating with the introduction of therapies able to stop human immunodeficiency virus (HIV) replication, or cure hepatitis C virus infections in people suffering from liver disease. However, there are important viral diseases without effective treatments, and the emergence of drug resistance threatens the efficacy of successful therapies used today. In this review, we discuss strategies to discover antiviral compounds specifically designed to combat drug resistance. Currently, efforts in this field are focused on targeted proteins (e.g. multi-target drug design strategies), but also on drug conformation (either improving drug positioning in the binding pocket or introducing conformational constraints), in the introduction or exploitation of new binding sites, or in strengthening interaction forces through the introduction of multiple hydrogen bonds, covalent binding, halogen bonds, additional van der Waals forces or multivalent binding. Among the new developments, proteolysis targeting chimeras (PROTACs) have emerged as a valid approach taking advantage of intracellular mechanisms involving protein degradation by the ubiquitin-proteasome system. Finally, several molecules targeting host factors (e.g. human dihydroorotate dehydrogenase and DEAD-box polypeptide 3) have been identified as broad-spectrum antiviral compounds. Implementation of herein described medicinal chemistry strategies are expected to contribute to the discovery of new drugs effective against current and future threats due to emerging and re-emerging viral pandemics.
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http://dx.doi.org/10.1039/d0cs01084gDOI Listing
April 2021

Identification of novel potent HIV-1 inhibitors by exploiting the tolerant regions of the NNRTIs binding pocket.

Eur J Med Chem 2021 Mar 24;214:113204. Epub 2021 Jan 24.

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012 Jinan, Shandong, PR China; China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, 44 West Culture Road, 250012 Jinan, Shandong, PR China. Electronic address:

With our previously identified potent NNRTIs 25a and HBS-11c as leads, series of novel thiophene[3,2-d]pyrimidine and thiophene[2,3-d]pyrimidine derivatives were designed via molecular hybridization strategy. All the target compounds were evaluated for their anti-HIV-1 activity and cytotoxicity in MT-4 cells. Compounds 16a1 and 16b1 turned out to be the most potent inhibitors against WT and mutant HIV-1 strains (L100I, K103N, and E138K), with EC values ranging from 0.007 μM to 0.043 μM. Gratifyingly, 16b1 exhibited significantly reduced cytotoxicity (CC > 217.5 μM) and improved water solubility (S = 49.3 μg/mL at pH 7.0) compared to the lead 25a (S < 1 μg/mL at pH 7.0, CC = 2.30 μM). Moreover, molecular docking was also conducted to rationalize the structure-activity relationships of these novel derivatives and to understand their key interactions with the binding pocket.
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http://dx.doi.org/10.1016/j.ejmech.2021.113204DOI Listing
March 2021

Mortality risk of COVID-19 in elderly males with comorbidities: a multi-country study.

Aging (Albany NY) 2020 12 31;13(1):27-60. Epub 2020 Dec 31.

Institute of Hepatology and Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha, China.

The COVID-19 pandemic causes severe morbidity and mortality. This multi-country study aimed to explore risk factors that drive mortality in COVID-19 patients who received neither dexamethasone nor remdesivir. We analyzed a cohort of 568 survivors and 507 non-survivors from China, European regions, and North America. Elderly males ≥70 years accounted for only 25% of survivors, but this rate was significantly higher in non-survivors from China (55%), European regions (63%), and North America (47%). Compared with survivors, non-survivors had more incidences of comorbidities such as cerebrovascular disease and chronic obstructive pulmonary disease (COPD, p-values<0.05). Survival analyses revealed age, male gender, shortness of breath, cerebrovascular disease, and COPD as mortality-associated factors. Survival time from symptom onset was significantly shorter in elderly versus young patients (median: 29 versus 62 days), males versus females (median: 46 versus 59 days), and patients with versus without comorbidities (mean: 41 versus 61 days). Mortality risk was higher in elderly males with comorbidities than in young females without comorbidities (p-value<0.01). Elderly male survivors with comorbidities also had longer hospital stays than other survivors (25 versus 18.5 days, p-value<0.01). Overall, the high mortality risk in elderly males with COVID-19-associated comorbidities supports early prevention and critical care for elderly populations.
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http://dx.doi.org/10.18632/aging.202456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835001PMC
December 2020

Novel indolylarylsulfone derivatives as covalent HIV-1 reverse transcriptase inhibitors specifically targeting the drug-resistant mutant Y181C.

Bioorg Med Chem 2021 01 10;30:115927. Epub 2020 Dec 10.

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan 250012, PR China. Electronic address:

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are widely used in combination therapies against HIV-1. However, emergent and transmitted drug resistance compromise their efficacy in the clinical setting. Y181C is selected in patients receiving nevirapine, etravirine and rilpivirine, and together with K103N is the most prevalent NNRTI-associated mutation in HIV-infected patients. Herein, we report on the design, synthesis and biological evaluation of a novel series of indolylarylsulfones bearing acrylamide or ethylene sulfonamide reactive groups as warheads to inactivate Cys181-containing HIV-1 RT via a Michael addition reaction. Compounds I-7 and I-9 demonstrated higher selectivity towards the Y181C mutant than against the wild-type RT, in nucleotide incorporation inhibition assays. The larger size of the NNRTI binding pocket in the mutant enzyme facilitates a better fit for the active compounds, while stacking interactions with Phe227 and Pro236 contribute to inhibitor binding. Mass spectrometry data were consistent with the covalent modification of the RT, although off-target reactivity constitutes a major limitation for further development of the described inhibitors.
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http://dx.doi.org/10.1016/j.bmc.2020.115927DOI Listing
January 2021

Design, synthesis, and evaluation of "dual-site"-binding diarylpyrimidines targeting both NNIBP and the NNRTI adjacent site of the HIV-1 reverse transcriptase.

Eur J Med Chem 2021 Feb 10;211:113063. Epub 2020 Dec 10.

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012 Jinan, Shandong, PR China; China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, 44 West Culture Road, 250012 Jinan, Shandong, PR China. Electronic address:

Inspired by our previous efforts to improve the drug-resistance profiles of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs), a novel series of "dual-site" binding diarylpyrimidine (DAPY) derivatives targeting both the NNRTI adjacent site and NNRTIs binding pocket (NNIBP) were designed, synthesized, and evaluated for their anti-HIV potency in TZM-bl and MT-4 cells. Eight compounds exhibited moderate to excellent potencies in inhibiting wild-type (WT) HIV-1 replication with EC values ranging from 2.45 nM to 5.36 nM, and 14c (EC = 2.45 nM) proved to be the most promising inhibitor. Of note, 14c exhibited potent activity against the single mutant strain E138K (EC = 10.6 nM), being comparable with ETR (EC = 9.80 nM) and 3.5-fold more potent than that of compound 7 (EC = 37.3 nM). Moreover, 14c acted as a classical NNRTI with high affinity for WT HIV-1 RT (IC = 0.0589 μM). The detailed structure-activity relationships (SARs) of the representative compounds were also determined, and further supported by molecular dynamics simulation. Overall, we envision that the "dual-site"-binding NNRTIs have significant prospects and pave the way for the next round of rational design of potent anti-HIV-1 agents.
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http://dx.doi.org/10.1016/j.ejmech.2020.113063DOI Listing
February 2021

Exploiting the tolerant region I of the non-nucleoside reverse transcriptase inhibitor (NNRTI) binding pocket. Part 2: Discovery of diarylpyrimidine derivatives as potent HIV-1 NNRTIs with high Fsp values and favorable drug-like properties.

Eur J Med Chem 2021 Mar 27;213:113051. Epub 2020 Nov 27.

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012, Ji'nan, Shandong, PR China; China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong, Province, 44 West Culture Road, 250012, Jinan, Shandong, PR China. Electronic address:

To yield potent HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) with favorable drug-like properties, a series of novel diarylpyrimidine derivatives targeting the tolerant region I of the NNRTI binding pocket were designed, synthesized and biologically evaluated. The most active inhibitor 10c exhibited outstanding antiviral activity against most of the viral panel, being about 2-fold (wild-type, EC = 0.0021 μM), 1.7-fold (K103N, EC = 0.0019 μM), and slightly more potent (E138K, EC = 0.0075 μM) than the NNRTI drug etravirine (ETR). Additionally, 10c was endowed with relatively low cytotoxicity (CC = 18.52 μM). More importantly, 10c possessed improved drug-like properties compared to those of ETR with an increased Fsp (Fraction of sp carbon atoms) value. Furthermore, the molecular dynamics simulation and molecular docking studies were implemented to reveal the binding mode of 10c in the binding pocket. Taken together, 10c is a promising lead compound that is worth further investigation.
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http://dx.doi.org/10.1016/j.ejmech.2020.113051DOI Listing
March 2021

Broad-Spectrum Antiviral Activity of 3'-Deoxy-3'-Fluoroadenosine against Emerging Flaviviruses.

Antimicrob Agents Chemother 2021 01 20;65(2). Epub 2021 Jan 20.

Department of Virology, Veterinary Research Institute, Brno, Czech Republic.

Emerging flaviviruses are causative agents of severe and life-threatening diseases, against which no approved therapies are available. Among the nucleoside analogues, which represent a promising group of potentially therapeutic compounds, fluorine-substituted nucleosides are characterized by unique structural and functional properties. Despite having first been synthesized almost 5 decades ago, they still offer new therapeutic opportunities as inhibitors of essential viral or cellular enzymes active in nucleic acid replication/transcription or nucleoside/nucleotide metabolism. Here, we report evaluation of the antiflaviviral activity of 28 nucleoside analogues, each modified with a fluoro substituent at different positions of the ribose ring and/or heterocyclic nucleobase. Our antiviral screening revealed that 3'-deoxy-3'-fluoroadenosine exerted a low-micromolar antiviral effect against tick-borne encephalitis virus (TBEV), Zika virus, and West Nile virus (WNV) (EC values from 1.1 ± 0.1 μM to 4.7 ± 1.5 μM), which was manifested in host cell lines of neural and extraneural origin. The compound did not display any measurable cytotoxicity up to concentrations of 25 μM but had an observable cytostatic effect, resulting in suppression of cell proliferation at concentrations of >12.5 μM. Novel approaches based on quantitative phase imaging using holographic microscopy were developed for advanced characterization of antiviral and cytotoxic profiles of 3'-deoxy-3'-fluoroadenosine In addition to its antiviral activity in cell cultures, 3'-deoxy-3'-fluoroadenosine was active in mouse models of TBEV and WNV infection. Our results demonstrate that fluoro-modified nucleosides represent a group of bioactive molecules with excellent potential to serve as prospective broad-spectrum antivirals in antiviral research and drug development.
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http://dx.doi.org/10.1128/AAC.01522-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848998PMC
January 2021

Antibody seroconversion in asymptomatic and symptomatic patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Clin Transl Immunology 2020 26;9(9):e1182. Epub 2020 Sep 26.

Department of Laboratory Medicine The Second Xiangya Hospital Central South University Changsha China.

Objectives: Asymptomatic and symptomatic patients may transmit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but their clinical features and immune responses remain largely unclear. We aimed to characterise the clinical features and immune responses of asymptomatic and symptomatic patients infected with SARS-CoV-2.

Methods: We collected clinical, laboratory and epidemiological records of patients hospitalised in a coronavirus field hospital in Wuhan. We performed qualitative detection of anti-SARS-CoV-2 immunoglobulin M (IgM) and immunoglobulin G (IgG) using archived blood samples.

Results: Of 214 patients with SARS-CoV-2, 26 (12%) were asymptomatic at hospital admission and during hospitalisation. Most asymptomatic patients were ≤ 60 years (96%) and females (65%) and had few comorbidities (< 16%). Serum levels of white and red blood cells were higher in asymptomatic than in symptomatic patients (-values < 0.05). During hospitalisation, IgG seroconversion was commonly observed in both asymptomatic and symptomatic patients (85% versus 94%, -value = 0.07); in contrast, IgM seroconversion was less common in asymptomatic than in symptomatic patients (31% versus 74%, -value < 0.001). The median time from the first virus-positive screening to IgG or IgM seroconversion was significantly shorter in asymptomatic than in symptomatic patients (median: 7 versus 14 days, -value < 0.01). Furthermore, IgG/IgM seroconversion rates increased concomitantly with the clearance of SARS-CoV-2 in both asymptomatic and symptomatic patients. At the time of virus clearance, IgG/IgM titres and plasma neutralisation capacity were significantly lower in recovered asymptomatic than in recovered symptomatic patients (-values < 0.01).

Conclusion: Asymptomatic and symptomatic patients exhibited different kinetics of IgG/IgM responses to SARS-CoV-2. Asymptomatic patients may transmit SARS-CoV-2, highlighting the importance of early diagnosis and treatment.
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http://dx.doi.org/10.1002/cti2.1182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519951PMC
September 2020

Targeting dual tolerant regions of binding pocket: Discovery of novel morpholine-substituted diarylpyrimidines as potent HIV-1 NNRTIs with significantly improved water solubility.

Eur J Med Chem 2020 Nov 10;206:112811. Epub 2020 Sep 10.

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China; China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, 44 West Culture Road, 250012, Jinan, Shandong, PR China. Electronic address:

To address the intractable issues of drug resistance and poor solubility, a novel series of morpholine-substituted diarylpyrimidines targeting the tolerant region I and tolerant region II of NNIBP were rationally designed by utilizing the available crystallography studies. The biological evaluation results showed that four most promising compounds (14e1, 14g1, 14g2 and 14j2) displayed excellent potency against WT HIV-1 strain with EC values ranging from 58 to 87 nM, being far more potent than NVP and comparable to ETV. Besides, some derivatives exhibited moderate activity in inhibiting the mutant HIV-1 strains. More encouragingly, 14d2 (RF = 0.4) possessed higher antiresistance profile than ETV (RF = 6.3) and K-5a2 (RF = 3.0) toward the double mutant strain F227L + V106A. The HIV-1 RT inhibition assay confirmed their binding target. The molecular docking studies were conducted and discussed in detail to rationalize the preliminary SARs. Further test indicated that morpholine could indeed promote the improvement of water solubility. Additionally, the in silico prediction of physicochemical properties and CYP enzymatic inhibitory ability were investigated to evaluate their drug-like features.
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http://dx.doi.org/10.1016/j.ejmech.2020.112811DOI Listing
November 2020

Danoprevir for the Treatment of Hepatitis C Virus Infection: Design, Development, and Place in Therapy.

Drug Des Devel Ther 2020 14;14:2759-2774. Epub 2020 Jul 14.

Hunan Provincial Key Laboratory of Clinical Epidemiology, Xiangya School of Public Health, Central South University, Changsha 410078, People's Republic of China.

On June 8, 2018, an NS3/4A protease inhibitor called danoprevir was approved in China to treat the infections of HCV genotype (GT) 1b - the most common HCV genotype worldwide. Based on phase 2 and 3 clinical trials, the 12-week regimen of ritonavir-boosted danoprevir (danoprevir/r) plus peginterferon alpha-2a and ribavirin offered 97.1% (200/206) of sustained virologic response at post-treatment week 12 (SVR12) in treatment-naïve non-cirrhotic patients infected with HCV genotype 1b. Adverse events such as anemia, fatigue, fever, and headache were associated with the inclusion of peginterferon alpha-2a and ribavirin in the danoprevir-based regimen. Moreover, drug resistance to danoprevir could be traced to amino acid substitutions (Q80K/R, R155K, D168A/E/H/N/T/V) near the drug-binding pocket of HCV NS3 protease. Despite its approval, the clinical use of danoprevir is currently limited to its combination with peginterferon alpha-2a and ribavirin, thereby driving its development towards interferon-free, ribavirin-free regimens with improved tolerability and adherence. In the foreseeable future, pan-genotypic direct-acting antivirals with better clinical efficacy and less adverse events will be available to treat HCV infections worldwide.
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http://dx.doi.org/10.2147/DDDT.S254754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368560PMC
July 2020

Design, synthesis, and biological evaluation of piperidinyl-substituted [1,2,4]triazolo[1,5-a]pyrimidine derivatives as potential anti-HIV-1 agents with reduced cytotoxicity.

Chem Biol Drug Des 2021 Jan 3;97(1):67-76. Epub 2020 Aug 3.

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Ji'nan, China.

Taking the previously reported compound BH-7d as the lead, we designed and synthesized a series of piperidinyl-substituted [1,2,4]triazolo[1,5-a]pyrimidines, and their anti-HIV activities as well as cytotoxicities were evaluated. Several compounds exhibited moderate anti-HIV (IIIB) potency, among which 2b was the most active one (EC  = 4.29 μM). Structure-activity relationships derived from the antiretroviral results were analyzed. Additionally, most compounds demonstrated reduced cytotoxicity (CC  > 200 μM) compared with those of BH-7d and etravirine. Molecular docking study further revealed the binding conformation of 2b in the binding pocket of HIV-1 reverse transcriptase.
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http://dx.doi.org/10.1111/cbdd.13760DOI Listing
January 2021

Bioisosterism-based design and enantiomeric profiling of chiral hydroxyl-substituted biphenyl-diarylpyrimidine nonnucleoside HIV-1 reverse transcriptase inhibitors.

Eur J Med Chem 2020 Sep 2;202:112549. Epub 2020 Jul 2.

Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China; Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai, 200433, China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai, 200433, China; Institute of Pharmaceutical Science and Technology, Zhejiang University of Technology, 18 Chao Wang Road, 310014, Hangzhou, China. Electronic address:

The single enantiomers of seven hydroxyl-substituted biphenyl-diarylpyrimidines were designed and synthesized by a bioisosterism strategy as novel HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). The cellular and enzymatic assays indicated that the novel obtained compounds had significant activities and relatively low cytotoxicity. The supercritical fluid chromatography (SFC) enantioseparations of the racemic compounds and the enantiomeric profiling resulted that the (S) forms were generally more potent than the (R) counterparts. Among all the chiral derivatives, (S)-(-)-12a showed the best potency with the antiviral activities against wild-type (WT) and single mutant strains (L100I, K103 N, Y181C, E138K; especially Y188L), and RT enzyme in the low nanomolar concentration range. Toward double mutant virus strains (F227L + V106A, RES056), (S)-(-)-12a possessed submicromolar antiviral activities. In addition, (S)-(-)-12a showed a high cell-based selectivity index (SI  = 5822) and no apparent toxicity was observed in the in vivo acute toxicity assay and electrocardiogram. The molecular docking studies predicted the binding modes of the compounds with RT and explained the activity differences for the enantiomers. Although the rat pharmacokinetic assay indicated a poor oral metabolism of the hydroxyl compound, the promising antiviral activity of the chiral hydroxyl-substituted biphenyl-diarylpyrimidines provided valuable lead compounds for further anti-HIV drug design.
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http://dx.doi.org/10.1016/j.ejmech.2020.112549DOI Listing
September 2020

Development of non-nucleoside reverse transcriptase inhibitors (NNRTIs): our past twenty years.

Acta Pharm Sin B 2020 Jun 21;10(6):961-978. Epub 2019 Nov 21.

Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, China.

Human immunodeficiency virus (HIV) is the primary infectious agent of acquired immunodeficiency syndrome (AIDS), and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are the cornerstone of HIV treatment. In the last 20 years, our medicinal chemistry group has made great strides in developing several distinct novel NNRTIs, including 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT), thio-dihydro-alkoxy-benzyl-oxopyrimidine (-DABO), diaryltriazine (DATA), diarylpyrimidine (DAPY) analogues, and their hybrid derivatives. Application of integrated modern medicinal strategies, including structure-based drug design, fragment-based optimization, scaffold/fragment hopping, molecular/fragment hybridization, and bioisosterism, led to the development of several highly potent analogues for further evaluations. In this paper, we review the development of NNRTIs in the last two decades using the above optimization strategies, including their structure-activity relationships, molecular modeling, and their binding modes with HIV-1 reverse transcriptase (RT). Future directions and perspectives on the design and associated challenges are also discussed.
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http://dx.doi.org/10.1016/j.apsb.2019.11.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332669PMC
June 2020

Discovery of potential dual-target prodrugs of HIV-1 reverse transcriptase and nucleocapsid protein 7.

Bioorg Med Chem Lett 2020 08 26;30(16):127287. Epub 2020 May 26.

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Ji'nan 250012, China. Electronic address:

In the present work, we described the design, synthesis and biological evaluation of a novel series of potential dual-target prodrugs targeting the HIV-1 reverse transcriptase (RT) and nucleocapsid protein 7 (NCp7) simultaneously. Among them, the most effective compound 7c was found to inhibit HIV-1 wild-type (WT) strain at double-digit nanomolar concentration (EC = 42 nM) in MT-4 cells, and sub-micromole (EC = 0.308 μM) to inhibit HIV-1 NL4-3 strain in TZM-bl cells. This is a significant improvement over the parent drug MT. In addition, it showed moderate inhibitory potency (EC = 1.329 μM) against the HIV-1 K103N/Y181C double mutant strain (MT-4 cells). The metabolic stability in human plasma of compound 7c indicated that it can release the active forms of the parent drugs MT and AZT in a linear time-independent manner and turn out to be a potential prodrug.
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http://dx.doi.org/10.1016/j.bmcl.2020.127287DOI Listing
August 2020

Structure-Activity Relationship Exploration of NNIBP Tolerant Region I Leads to Potent HIV-1 NNRTIs.

ACS Infect Dis 2020 08 17;6(8):2225-2234. Epub 2020 Jul 17.

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012 Jinan, Shandong, PR China.

Previous efforts in our lab have led to the development of human immunodeficiency virus type 1 (HIV-1) non-nucleoside reverse transcriptase inhibitor (NNRTI) thiophene[3,2-]pyrimidine compound () with promising activity against wild-type and mutant HIV-1 strains. In this work, a series of novel diarylpyrimidines derivatives carrying a structurally diverse motif at the right wing of the lead was designed and synthesized as potential anti-HIV-1 agents. The results demonstrated that yielded exceptionally potent activity against HIV-1 wild-type (50% effective concentration (EC) = 3.30 nM) and mutant strain RES056 (EC = 22.6 nM) in MT-4 cells; in the reverse transcriptase inhibitory assay, (half maximal inhibitory concentration (IC) = 0.028 μM) was remarkably superior to that of (IC = 0.300 μM) and comparable to that of etravirine (ETR; IC = 0.011 μM). Notably, exhibited better druggability than that of , including significantly reduced CYP enzymatic inhibitory activity (IC > 50 μM), lower human ether-à-go-go related gene (hERG) inhibition (IC > 30 μM), and improved metabolic stability (short half-life, = 77.5 min) .
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http://dx.doi.org/10.1021/acsinfecdis.0c00327DOI Listing
August 2020

Clinical characteristics of older and younger patients infected with SARS-CoV-2.

Aging (Albany NY) 2020 06 22;12(12):11296-11305. Epub 2020 Jun 22.

Institute of Hepatology and Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.

Background: SARS-CoV-2 causes high mortality risk in older patients. This study aims to characterize the clinical features of older and younger SARS-CoV-2 infected patients.

Results: A total of 239 patients were divided into the younger group (<60 years; n=181) and the older group (≥60 years; n=58). In both groups, fever and cough were common symptoms. However, dyspnea was more frequent in older patients than younger patients (20.7% versus 9.9%, p=0.032). Compared with younger patients, older patients harbored more severe cases (37.9% versus 17.1%, p=0.001) and comorbidities (58.6% versus 21.0%, p<0.001) such as hypertension and diabetes. The baseline values of eosinophils and C-reactive protein were abnormal in older and younger groups. From baseline to day 14, significant decreases of three biomarkers (C-reactive protein, hemoglobin, albumin) and dramatic increases of three biomarkers (lymphocytes, platelets, blood urea nitrogen) were observed in older patients.

Conclusion: Older and younger patients exhibited differences in dyspnea, comorbidities, and proportions of severe cases. Moreover, the disease progression of SARS-CoV-2 in older patients is observed with the dynamics of laboratory biomarkers, supporting their potential use in disease monitoring.

Methods: We retrieved clinical symptoms, laboratory findings, comorbidities, and hospitalization information of SARS-CoV-2 cases in Changsha.
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http://dx.doi.org/10.18632/aging.103535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343458PMC
June 2020

Exploring the hydrophobic channel of NNIBP leads to the discovery of novel piperidine-substituted thiophene[3,2-]pyrimidine derivatives as potent HIV-1 NNRTIs.

Acta Pharm Sin B 2020 May 14;10(5):878-894. Epub 2019 Sep 14.

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China.

In this report, a series of novel piperidine-substituted thiophene[3,2-]pyrimidine derivatives were designed to explore the hydrophobic channel of the non-nucleoside reverse transcriptase inhibitors binding pocket (NNIBP) by incorporating an aromatic moiety to the left wing of the lead . The newly synthesized compounds were evaluated for anti-HIV potency in MT-4 cells and inhibitory activity to HIV-1 reverse transcriptase (RT). Most of the synthesized compounds exhibited broad-spectrum activity toward wild-type and a wide range of HIV-1 strains carrying single non-nucleoside reverse transcriptase inhibitors (NNRTI)-resistant mutations. Especially, compound exhibited the most potent activity against wild-type and a panel of single mutations (L100I, K103N, Y181C, Y188L and E138K) with an EC ranging from 6.02 to 23.9 nmol/L, which were comparable to those of etravirine (ETR). Moreover, the RT inhibition activity, preliminary structure-activity relationship and molecular docking were also investigated. Furthermore, exhibited favorable pharmacokinetics (PK) profiles and with a bioavailability of 33.8%. Taken together, the results could provide valuable insights for further optimization and compound holds great promise as a potential drug candidate for the treatment of HIV-1 infection.
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http://dx.doi.org/10.1016/j.apsb.2019.08.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280082PMC
May 2020

Privileged scaffold inspired design of novel oxime-biphenyl-DAPYs in treatment of HIV-1.

Bioorg Chem 2020 06 8;99:103825. Epub 2020 Apr 8.

Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, People's Republic of China; Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, People's Republic of China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, People's Republic of China; Institute of Pharmaceutical Science and Technology, Zhejiang University of Technology Hangzhou 310014, People's Republic of China. Electronic address:

Oxime is a key pharmacophore in drug development. The biphenyl diarylpyrimidines (DAPYs) have been developed by our group as novel non-nucleoside reverse transcriptase inhibitors (NNRTIs). In this study, fourteen oxime-biphenyl-DAPYs were designed and synthesized through a privileged scaffold inspired design strategy. They exhibited promising activity toward wild type HIV-1 and single mutant strains. Compound 7d was found to be the most potent one against both wild type (EC = 12.1 nM) and E138K mutant strains (EC = 0.0270 µM). It also had a much lower cytotoxicity (CC > 292 µM) and higher selective index (SI > 24105) than those of the FDA-approved drugs efavirenz and etravirine. Molecular docking and dynamics simulation predicted and disclosed the binding mode of compound 7d with the RT, providing the explanation on the antiviral activity. These results were helpful for subsequent structural optimizations in anti-HIV-1 drug discovery.
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http://dx.doi.org/10.1016/j.bioorg.2020.103825DOI Listing
June 2020

Letter to the editor.

Authors:
Erik De Clercq

Life Sci 2020 Jul 22;252:117714. Epub 2020 Apr 22.

KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Herestraat 49, B-3000 Leuven, Belgium. Electronic address:

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http://dx.doi.org/10.1016/j.lfs.2020.117714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7174986PMC
July 2020

Design, Synthesis, and Mechanism Study of Benzenesulfonamide-Containing Phenylalanine Derivatives as Novel HIV-1 Capsid Inhibitors with Improved Antiviral Activities.

J Med Chem 2020 05 29;63(9):4790-4810. Epub 2020 Apr 29.

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Ji'nan, Shandong 250012, People's Republic of China.

The HIV-1 CA protein has gained remarkable attention as a promising therapeutic target for the development of new antivirals, due to its pivotal roles in HIV-1 replication (structural and regulatory). Herein, we report the design and synthesis of three series of benzenesulfonamide-containing phenylalanine derivatives obtained by further structural modifications of to aid in the discovery of more potent and drug-like HIV-1 CA inhibitors. Structure-activity relationship studies of these compounds led to the identification of new phenylalanine derivatives with a piperazinone moiety, represented by compound , which exhibited anti-HIV-1 activity 5.78-fold better than . Interestingly, also showed anti-HIV-2 activity (EC = 31 nM), with almost 120 times increased potency over . However, due to the higher significance of HIV-1 as compared to HIV-2 for the human population, this manuscript focuses on the mechanism of action of our compounds in the context of HIV-1. SPR studies on representative compounds confirmed CA as the binding target. The action stage determination assay demonstrated that these inhibitors exhibited antiviral activities with a dual-stage inhibition profile. The early-stage inhibitory activity of compound was 6.25 times more potent as compared to but appeared to work via the accelerating capsid core assembly rather than stabilization. However, the mechanism by which they exert their antiviral activity in the late stage appears to be the same as with less infectious HIV-1 virions produced in their presence, as judged p24 content studies. MD simulations provided the key rationale for the promising antiviral potency of . Additionally, exhibited a modest increase in HLM and human plasma metabolic stabilities as compared to , as well as a moderately improved pharmacokinetic profile, favorable oral bioavailability, and no acute toxicity. These studies provide insights and serve as a starting point for subsequent medicinal chemistry efforts in optimizing these promising HIV inhibitors.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011991PMC
May 2020

Structure-Based Bioisosterism Yields HIV-1 NNRTIs with Improved Drug-Resistance Profiles and Favorable Pharmacokinetic Properties.

J Med Chem 2020 05 22;63(9):4837-4848. Epub 2020 Apr 22.

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Jinan, Shandong, P.R. China.

The development of efficacious NNRTIs for AIDS therapy commonly encountered the rapid generation of drug-resistant mutations, which becomes a major impediment to effective anti-HIV treatment. Using a structure-based bioisosterism strategy, a series of piperidine-substituted thiophene[2,3-]pyrimidine derivatives were designed and synthesized. Compound yielded the greatest potency, exhibiting significantly better anti-HIV-1 activity than against all of the tested NNRTI-resistant HIV-1 strains. In addition, the phenotypic (cross)resistance of and other NRTIs to the different selected HIV-1 strains was evaluated. As expected, no phenotypic cross-resistance against the NRTIs (AZT and PMPA) was observed with the mutant strain. Furthermore, was identified with improved solubility, lower CYP liability, and hERG inhibition. Remarkably, exhibited optimal pharmacokinetic properties in rats ( = 37.06%) and safety in mice (LD > 2000 mg/kg), which highlights as a promising anti-HIV-1 drug candidate.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00117DOI Listing
May 2020

Scaffold Hopping in Discovery of HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors: From CH(CN)-DABOs to CH(CN)-DAPYs.

Molecules 2020 Mar 30;25(7). Epub 2020 Mar 30.

Institute of Pharmaceutical Science and Technology, Zhejiang University of Technology, Hangzhou 310014, China.

Scaffold hopping is a frequently-used strategy in the development of non-nucleoside reverse transcriptase inhibitors. Herein, CH(CN)-DAPYs were designed by hopping the cyano-methylene linker of our previous published CH(CN)-DABOs onto the etravirine (ETR). Eighteen CH(CN)-DAPYs were synthesized and evaluated for their anti-HIV activity. Most compounds exhibited promising activity against wild-type (WT) HIV-1. Compounds (EC = 6 nM) and (EC = 8 nM) showed single-digit nanomolar potency against WT HIV-1. Moreover, these two compounds had EC values of 0.06 and 0.08 μM toward the K103N mutant, respectively, which were comparable to the reference efavirenz (EFV) (EC = 0.08 μM). The preliminary structure-activity relationship (SAR) indicated that introducing substitutions on C2 of the 4-cyanophenyl group could improve antiviral activity. Molecular docking predicted that the cyano-methylene linker was positioned into the hydrophobic cavity formed by Y181/Y188 and V179 residues.
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http://dx.doi.org/10.3390/molecules25071581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7180830PMC
March 2020

In situ click chemistry-based rapid discovery of novel HIV-1 NNRTIs by exploiting the hydrophobic channel and tolerant regions of NNIBP.

Eur J Med Chem 2020 May 14;193:112237. Epub 2020 Mar 14.

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China; China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, 44 West Culture Road, 250012, Jinan, Shandong, PR China.

HIV-1 RT has been considered as one of the most important targets for the development of anti-HIV-1 drugs for their well-solved three-dimensional structure and well-known mechanism of action. In this study, with HIV-1 RT as target, we used miniaturized parallel click chemistry synthesis via CuAAC reaction followed by in situ biological screening to discover novel potent HIV-1 NNRTIs. A 156 triazole-containing inhibitor library was assembled in microtiter plates and in millimolar scale. The enzyme inhibition screening results showed that 22 compounds exhibited improved inhibitory activity. Anti-HIV-1 activity results demonstrated that A3N19 effected the most potent activity against HIV-1 IIIB (EC = 3.28 nM) and mutant strain RES056 (EC = 481 nM). The molecular simulation analysis suggested that the hydrogen bonding interactions of A3N19 with the main chain of Lys101 and Lys104 was responsible for its potency. Overall, the results indicated the in situ click chemistry-based strategy was rational and might be amenable for the future discovery of more potent HIV-1 NNRTIs.
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http://dx.doi.org/10.1016/j.ejmech.2020.112237DOI Listing
May 2020