Publications by authors named "Xujie Zhang"

16 Publications

  • Page 1 of 1

An insight on medicinal aspects of novel HIV-1 capsid protein inhibitors.

Eur J Med Chem 2021 May 15;217:113380. Epub 2021 Mar 15.

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:

A capsid is the protein shell of a virus, encircling its genetic material. The HIV capsid is erected from a single protein, known as capsid protein. The capsid of HIV-1 significantly involved in many processes of the virus life cycle, which makes it as a novel target for the new inhibitors. Recently many novel HIV-1 inhibitors binding to capsid proteins have been reported successfully. Most of these inhibitors can inhibit or accelerate the disassembly or assembly of the capsid, and some of them can inhibit reverse transcription. Unfortunately, none of them are currently approved by U.S. FDA. However, GS-6207, an inhibitor binds to the NTD-CTD interface with potent antiviral activity and the long metabolic cycle, is expected to be the first approved drug targeting HIV-1 capsid. Herein, we provide a concise report focusing on the recent prospective of HIV-1 capsid inhibitors in medicinal chemistry in order to enlighten drug design.
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http://dx.doi.org/10.1016/j.ejmech.2021.113380DOI Listing
May 2021

[Application of biomechanical modeling and simulation in the development of non-invasive technologies and devices for cardiovascular testing].

Sheng Wu Yi Xue Gong Cheng Xue Za Zhi 2020 Dec;37(6):990-999

School of Naval Architecture, Ocean & Civil Engineering, Shanghai Jiao Tong University, Shanghai 200240, P.R.China.

The prevalence of cardiovascular disease in our country is increasing, and it has been a big problem affecting the social and economic development. It has been demonstrated that early intervention of cardiovascular risk factors can effectively reduce cardiovascular disease-caused mortality. Therefore, extensive implementation of cardiovascular testing and risk factor screening in the general population is the key to the prevention and treatment of cardiovascular disease. However, the categories of devices available for quick cardiovascular testing are limited, and in particular, many existing devices suffer from various technical problems, such as complex operation, unclear working principle, or large inter-individual variability in measurement accuracy, which lead to an overall low popularity and reliability of cardiovascular testing. In this study, we introduce the non-invasive measurement mechanisms and relevant technical progresses for several typical cardiovascular indices (e.g., peripheral/central arterial blood pressure, and arterial stiffness), with emphasis on describing the applications of biomechanical modeling and simulation in mechanism verification, analysis of influential factors, and technical improvement/innovation.
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http://dx.doi.org/10.7507/1001-5515.202008076DOI Listing
December 2020

Prevalence and predictors of anxiety and depressive symptoms among patients diagnosed with oral cancer in China: a cross-sectional study.

BMC Psychiatry 2020 08 5;20(1):394. Epub 2020 Aug 5.

Department of Nursing, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, P.R. China.

Background: Anxiety and depression are common mental health problems among patients with cancer. While many psychological variables have been proven to influence anxiety and depressive symptoms, the variables are not mutually exclusive and their integrated effects on patients with oral cancer are yet unknown. The present study aims to explore the prevalence of anxiety and depressive symptoms among patients with oral cancer, to find out key potentially predictive factors associated with anxiety and depressive symptoms.

Method: A cross-sectional study was carried out for Chinese patients with oral cancer between May 2016 and October 2017 in two Grade-A Tertiary Hospitals in Shenyang, China. Two hundred thirty patients with oral cancer were interviewed with questionnaires on demographic variables, Zung Self-Rating Anxiety Scale (SAS), Center for Epidemiologic Studies Depression Scale (CES-D), Herth Hope Index (HHI), Social Impact Scale, Multidimensional Scale of Perceived Social Support (MSPSS), Revised Life Orientation Test (LOT-R), Perceived Stress Scale-10 (PSS-10), and General Perceived Self-efficacy Scale(GSE). Chi-square test, nonparametric test, t-test and logistic regression analyses were conducted where appropriate to explore predictive factors of anxiety symptoms and depressive symptoms.

Results: The prevalence of anxiety symptoms and depressive symptoms in the sample population was 36.96% (85/230) and 65.21% (150/230), respectively. Social isolation dimension of stigma (β = 0.436, OR = 1.547, CI:1.211 ~ 1.975), optimism (β = - 0.276, OR = 0.759, CI:0.624 ~ 0.922), and perceived stress (β = 0.217, OR = 1.243, CI:1.092 ~ 1.414) were predictors of anxiety symptoms. Marriage (β = 1.648, OR = 5.198, CI:1.427 ~ 18.924), positive readiness and expectancy dimension of hope (β = - 0.505, OR = 0.604, CI:0.395 ~ 0.923), social isolation dimension of stigma (β = 0.314, OR = 1.368, CI:1.054 ~ 1.776) and perceived stress (β = 0.273, OR = 1.314, CI:1.134 ~ 1.524) were predictors of depressive symptoms among oral cancer patients.

Conclusion: The prevalence of anxiety symptoms and depressive symptoms was high among oral cancer patients in China. The communal predictors of anxiety and depressive symptoms in patients with oral cancer were levels of perceived stress and social isolation of stigma. In addition, optimism was a predictor of anxiety symptoms and hope was a predictor of depressive symptoms.

Trial Registration: 2015-16, registered 20 Dec 2015.
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http://dx.doi.org/10.1186/s12888-020-02796-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405439PMC
August 2020

Weakly Supervised Person Re-ID: Differentiable Graphical Learning and a New Benchmark.

IEEE Trans Neural Netw Learn Syst 2021 May 3;32(5):2142-2156. Epub 2021 May 3.

Person reidentification (Re-ID) benefits greatly from the accurate annotations of existing data sets (e.g., CUHK03 and Market-1501), which are quite expensive because each image in these data sets has to be assigned with a proper label. In this work, we ease the annotation of Re-ID by replacing the accurate annotation with inaccurate annotation, i.e., we group the images into bags in terms of time and assign a bag-level label for each bag. This greatly reduces the annotation effort and leads to the creation of a large-scale Re-ID benchmark called SYSU- 30k . The new benchmark contains 30k individuals, which is about 20 times larger than CUHK03 (1.3k individuals) and Market-1501 (1.5k individuals), and 30 times larger than ImageNet (1k categories). It sums up to 29606918 images. Learning a Re-ID model with bag-level annotation is called the weakly supervised Re-ID problem. To solve this problem, we introduce a differentiable graphical model to capture the dependencies from all images in a bag and generate a reliable pseudolabel for each person's image. The pseudolabel is further used to supervise the learning of the Re-ID model. Compared with the fully supervised Re-ID models, our method achieves state-of-the-art performance on SYSU- 30k and other data sets. The code, data set, and pretrained model will be available at https://github.com/wanggrun/SYSU-30k.
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http://dx.doi.org/10.1109/TNNLS.2020.2999517DOI Listing
May 2021

Spreading of benquitrione droplets on superhydrophobic leaves through pillar[5]arene-based host-guest chemistry.

Chem Commun (Camb) 2020 Jul 9;56(55):7593-7596. Epub 2020 Jun 9.

Key Laboratory of Pesticide and Chemical Biology (CCNU), Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, P. R. China.

Spreading of agricultural sprays on plant surfaces is a significant task as it helps decrease pesticide usage and thereby reduces the risk of environmental pollution. Here, we report a method of increasing the spreading of herbicide benquitrione droplets on superhydrophobic surfaces through its selective dynamic self-assembly with amino pillar[5]arenes. Supramolecular interaction such as host-guest interaction was utilized for the complete diffusion of benquitrione over the hydrophobic plant surface. Furthermore, molecular dynamics simulations were used to verify that AP5A improved the spreading of benquitrione droplets on superhydrophobic interfaces. Moreover, complexation of benquitrione did not affect its biological activity. The present work provides a new method for improving the utilization rate of pesticides and reducing pesticide use.
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http://dx.doi.org/10.1039/d0cc02187cDOI Listing
July 2020

5-Hydroxypyrido[2,3-b]pyrazin-6(5H)-one derivatives as novel dual inhibitors of HIV-1 reverse transcriptase-associated ribonuclease H and integrase.

Eur J Med Chem 2018 Jul 18;155:714-724. Epub 2018 Jun 18.

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

We reported herein the design, synthesis and biological evaluation of a series of 5-hydroxypyrido[2,3-b]pyrazin-6(5H)-one derivatives as HIV-1 reverse transcriptase (RT) ribonuclease H (RNase H) inhibitors using a privileged structure-guided scaffold refining strategy. In view of the similarities between the pharmacophore model of RNase H and integrase (IN) inhibitors as well as their catalytic sites, we also performed IN inhibition assays. Notably, the majority of these derivatives inhibited RNase H and IN at micromolar concentrations. Among them, compound 7a exhibited similar inhibitory activity against RNase H and IN (IC = 1.77 μM, IC = 1.18 μM, ratio = 1.50). To the best of our knowledge, this is the first reported dual HIV-1 RNase H-IN inhibitor based on a 5-hydroxypyrido[2,3-b]pyrazin-6(5H)-one structure. Molecular modeling has been used to predict the binding mode of 7a in complex with the catalytic cores of HIV-1 RNase H and IN. Taken together these results strongly support the feasibility of developing HIV-1 dual inhibitors from analog-based optimization of divalent metal ion chelators. Recently, the identification of dual inhibitors proved to be a highly effective strategy for novel antivirals discovery. Therefore, these compounds appear to be useful leads that can be further modified to develop more valuable anti-HIV-1 molecules with suitable drug profiles.
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http://dx.doi.org/10.1016/j.ejmech.2018.06.036DOI Listing
July 2018

Multi-Omics Analysis Reveals a Correlation between the Host Phylogeny, Gut Microbiota and Metabolite Profiles in Cyprinid Fishes.

Front Microbiol 2017 17;8:454. Epub 2017 Mar 17.

State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of SciencesWuhan, China; Freshwater Aquaculture Collaborative Innovation Center of Hubei Province, Huazhong Agricultural UniversityWuhan, China.

Gut microbiota play key roles in host nutrition and metabolism. However, little is known about the relationship between host genetics, gut microbiota and metabolic profiles. Here, we used high-throughput sequencing and gas chromatography/mass spectrometry approaches to characterize the microbiota composition and the metabolite profiles in the gut of five cyprinid fish species with three different feeding habits raised under identical husbandry conditions. Our results showed that host species and feeding habits significantly affect not only gut microbiota composition but also metabolite profiles (ANOSIM, ≤ 0.05). Mantel test demonstrated that host phylogeny, gut microbiota, and metabolite profiles were significantly related to each other ( ≤ 0.05). Additionally, the carps with the same feeding habits had more similarity in gut microbiota composition and metabolite profiles. Various metabolites were correlated positively with bacterial taxa involved in food degradation. Our results shed new light on the microbiome and metabolite profiles in the gut content of cyprinid fishes, and highlighted the correlations between host genotype, fish gut microbiome and putative functions, and gut metabolite profiles.
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http://dx.doi.org/10.3389/fmicb.2017.00454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5355437PMC
March 2017

Alterations of the gut microbiome of largemouth bronze gudgeon (Coreius guichenoti) suffering from furunculosis.

Sci Rep 2016 07 28;6:30606. Epub 2016 Jul 28.

State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China.

High-throughput sequencing was applied to compare the intestinal microbiota in largemouth bronze gudgeon either healthy or affected by furunculosis. Proteobacteria, Actinobacteria, Tenericutes, Firmicutes and Bacteroidetes were detected as the predominant bacterial phyla in the gut of both diseased and healthy fish. The abundance of Proteobacteria differed significantly between the two groups of fish, mainly due to the overwhelming prevalence of Aeromonas in the diseased fish (81% ± 17%), while the genus was unevenly spread among the apparently healthy fish (33% ± 33%). The bacterial diversity in the intestine of diseased fish was markedly lower than in healthy fish. Analysis revealed the significant dissimilarity between the gut microbiota of diseased and healthy fish. The bacterial profiles in the gut were further characterized with the 28 phylotypes that were shared by the two groups. In diseased fish, two shared OTUs (OTU0001 and OTU0013) were closely related to Aeromonas salmonicida, their total proportion exceeding 70% of the sequences in diseased fish, while averaging 5.2% ± 4.6% in the healthy fish. This result suggested the presence of healthy carriers of pathogenic A. salmonicida among the farmed fish, and the gut appeared as a probable infection source for furunculosis in largemouth bronze gudgeon.
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http://dx.doi.org/10.1038/srep30606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4964610PMC
July 2016

Early classic hemofiltration exhibits no benefits in severe acute pancreatitis with early organ failure: a retrospective case-matched study.

Artif Organs 2014 Apr 11;38(4):335-41. Epub 2013 Sep 11.

Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi Province, China.

Continuous venovenous hemofiltration (CVVH) is an important organ supportive technique. This study aimed to evaluate the impact of early classic CVVH on the outcomes of severe acute pancreatitis (SAP) patients with early organ failure (EOF). Between 2008 and 2012, a total of 44 SAP patients with EOF were admitted to our department. The 44 patients were classified into two groups according to whether they received early classic CVVH (2 L/h, initiated within 24 h after admission): 25 patients received early CVVH (ECVVH group), and 19 patients did not receive early CVVH (control group). The two groups were matched for age and Acute Physiology and Chronic Health Evaluation II scores. The severity of organ dysfunctions was evaluated by Sequential Organ Failure Assessment (SOFA) scores. Each group included 19 patients. The baseline characters between the two groups were balanced. The SOFA scores in the ECVVH group increased compared with those in the control group. The time to weaning from mechanical ventilation was significantly longer in the ECVVH group (log-rank test: χ(2)  = 4.007, P = 0.045). Renal support was also significantly prolonged in the ECVVH group (the number of patients receiving CVVH 72 h after admission: 10 vs. 3, respectively, P = 0.038). Nine patients died in the ECVVH group versus six patients in the control group (P = 0.508). In conclusion, our study failed to prove that early classic CVVH had any benefits on the outcomes of SAP patients with EOF. Unexpectedly, early classic CVVH worsened organ functional capacity. However, it is possible that CVVH using advanced techniques may be beneficial in SAP patients with EOF.
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http://dx.doi.org/10.1111/aor.12159DOI Listing
April 2014

Potential of lichen secondary metabolites against Plasmodium liver stage parasites with FAS-II as the potential target.

J Nat Prod 2013 Jun 19;76(6):1064-70. Epub 2013 Jun 19.

Department of Pharmaceutical and Biological Chemistry, School of Pharmacy, University of London, London WC1N 1AX, UK.

Chemicals targeting the liver stage (LS) of the malaria parasite are useful for causal prophylaxis of malaria. In this study, four lichen metabolites, evernic acid (1), vulpic acid (2), psoromic acid (3), and (+)-usnic acid (4), were evaluated against LS parasites of Plasmodium berghei. Inhibition of P. falciparum blood stage (BS) parasites was also assessed to determine stage specificity. Compound 4 displayed the highest LS activity and stage specificity (LS IC50 value 2.3 μM, BS IC50 value 47.3 μM). The compounds 1-3 inhibited one or more enzymes (PfFabI, PfFabG, and PfFabZ) from the plasmodial fatty acid biosynthesis (FAS-II) pathway, a potential drug target for LS activity. To determine species specificity and to clarify the mechanism of reported antibacterial effects, 1-4 were also evaluated against FabI homologues and whole cells of various pathogens (S. aureus, E. coli, M. tuberculosis). Molecular modeling studies suggest that lichen acids act indirectly via binding to allosteric sites on the protein surface of the FAS-II enzymes. Potential toxicity of compounds was assessed in human hepatocyte and cancer cells (in vitro) as well as in a zebrafish model (in vivo). This study indicates the therapeutic and prophylactic potential of lichen metabolites as antibacterial and antiplasmodial agents.
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http://dx.doi.org/10.1021/np400083kDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4119598PMC
June 2013

Is continuous venovenous hemofiltration effective against severe acute pancreatitis?

Artif Organs 2013 Jul 5;37(7):615-22. Epub 2013 Mar 5.

Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi, China.

Our aim was to investigate the efficacy of continuous venovenous hemofiltration (CVVH) in treating severe acute pancreatitis (SAP). A literature search was performed using PubMed (1992-present), and all studies investigating the efficacy of CVVH in treating SAP were included. Four comparative studies and seven case series comprising a total of 354 patients were included. The overall mortality rate of patients receiving CVVH was 20% (55/275). A decreased mortality rate and decreased serum cytokine levels were reported in the CVVH groups in only two studies. The starting time point, substitution fluid flow rate, filter membrane type, hemofilter change interval, anticoagulation, and sustaining times of CVVH varied among the studies, and the impact of these parameters on the efficacy of CVVH was poorly reported. High-volume CVVH, when started early, was demonstrated to be more effective in eliminating cytokines in only one study. After the application of CVVH, the patient conditions started to improve between the 6th and 72nd hours. In conclusion, no solid clinical evidence has proven the efficacy of CVVH in treating SAP. High-volume CVVH that is started early and sustained for at least 72 h may be adopted to investigate the efficacy of CVVH for treating SAP.
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http://dx.doi.org/10.1111/aor.12051DOI Listing
July 2013

Substrate recognition by β-ketoacyl-ACP synthases.

Biochemistry 2011 Dec 17;50(49):10678-86. Epub 2011 Nov 17.

Institute for Chemical Biology & Drug Discovery, Department of Chemistry, Stony Brook University, Stony Brook, New York 11794-3400, United States.

β-Ketoacyl-ACP synthase (KAS) enzymes catalyze Claisen condensation reactions in the fatty acid biosynthesis pathway. These reactions follow a ping-pong mechanism in which a donor substrate acylates the active site cysteine residue after which the acyl group is condensed with the malonyl-ACP acceptor substrate to form a β-ketoacyl-ACP. In the priming KASIII enzymes the donor substrate is an acyl-CoA while in the elongating KASI and KASII enzymes the donor is an acyl-ACP. Although the KASIII enzyme in Escherichia coli (ecFabH) is essential, the corresponding enzyme in Mycobacterium tuberculosis (mtFabH) is not, suggesting that the KASI or II enzyme in M. tuberculosis (KasA or KasB, respectively) must be able to accept a CoA donor substrate. Since KasA is essential, the substrate specificity of this KASI enzyme has been explored using substrates based on phosphopantetheine, CoA, ACP, and AcpM peptide mimics. This analysis has been extended to the KASI and KASII enzymes from E. coli (ecFabB and ecFabF) where we show that a 14-residue malonyl-phosphopantetheine peptide can efficiently replace malonyl-ecACP as the acceptor substrate in the ecFabF reaction. While ecFabF is able to catalyze the condensation reaction when CoA is the carrier for both substrates, the KASI enzymes ecFabB and KasA have an absolute requirement for an ACP substrate as the acyl donor. Provided that this requirement is met, variation in the acceptor carrier substrate has little impact on the k(cat)/K(m) for the KASI reaction. For the KASI enzymes we propose that the binding of ecACP (AcpM) results in a conformational change that leads to an open form of the enzyme to which the malonyl acceptor substrate binds. Finally, the substrate inhibition observed when palmitoyl-CoA is the donor substrate for the KasA reaction has implications for the importance of mtFabH in the mycobacterial FASII pathway.
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http://dx.doi.org/10.1021/bi201199xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3361727PMC
December 2011

Inhibiting enoyl-ACP reductase (FabI) across pathogenic microorganisms by linear sesquiterpene lactones from Anthemis auriculata.

Phytomedicine 2008 Dec;15(12):1125-9

Department of Pharmacognosy and Chemistry of Natural Products, School of Pharmacy, University of Athens, 157 71 Athens, Greece.

Enoyl-ACP reductase (FabI) is a key enzyme of the type II fatty acid biosynthesis (FAS-II) pathway and a validated antimicrobial target. In the current study, three linear sesquiterpene lactones obtained from Anthemis auriculata, namely anthecotulide (1), 4-hydroxyanthecotulide (2) and 4-acetoxyanthecotulide (3) were evaluated for specific inhibitory effects against the FabI enzyme from three pathogenic microorganisms, Plasmodium falciparum (PfFabI), Mycobacterium tuberculosis (MtFabI) and Escherichia coli (EcFabI). In addition, the compounds were also tested against two elongation enzymes from the plasmodial FAS-II system, beta-ketoacyl-ACP reductase (PfFabG) and beta-hydroxyacyl-ACP deydratase (PfFabZ). The compounds showed clear differentiation in inhibition of FabI enzymes from different microorganisms. Anthecotulide (1) was most active against MtFabI (IC(50) 4.5 microg/ml), whereas the oxygenated derivatives thereof (compounds 2 and 3) specifically inhibited plasmodial FAS-II enzymes, PfFabI and PfFabG (IC(50) values 20-75 microg/ml). All compounds were inactive towards EcFabI. In whole cell assays, all three compounds exhibited antimalarial and antibacterial activities.
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http://dx.doi.org/10.1016/j.phymed.2008.02.018DOI Listing
December 2008

Marine natural products from the Turkish sponge Agelas oroides that inhibit the enoyl reductases from Plasmodium falciparum, Mycobacterium tuberculosis and Escherichia coli.

Bioorg Med Chem 2007 Nov 22;15(21):6834-45. Epub 2007 Aug 22.

Centre for Pharmacognosy and Phytotherapy, School of Pharmacy, University of London, London, UK.

The type II fatty acid pathway (FAS-II) is a validated target for antimicrobial drug discovery. An activity-guided isolation procedure based on Plasmodium falciparum enoyl-ACP reductase (PfFabI) enzyme inhibition assay on the n-hexane-, the CHCl(3-) and the aq MeOH extracts of the Turkish marine sponge Agelas oroides yielded six pure metabolites [24-ethyl-cholest-5alpha-7-en-3-beta-ol (1), 4,5-dibromopyrrole-2-carboxylic acid methyl ester (2), 4,5-dibromopyrrole-2-carboxylic acid (3), (E)-oroidin (4), 3-amino-1-(2-aminoimidazoyl)-prop-1-ene (5), taurine (6)] and some minor, complex fatty acid mixtures (FAMA-FAMG). FAMA, consisting of a 1:2 mixture of (5Z,9Z)-5,9-tricosadienoic (7) and (5Z,9Z)-5,9-tetracosadienoic (8) acids, and FAMB composed of 8, (5Z,9Z)-5,9-pentacosadienoic (9) and (5Z,9Z)-5,9-hexacosadienoic (10) acids in approximately 3:3:2 ratio were the most active PfFabI inhibitory principles of the hexane extract (IC(50) values 0.35 microg/ml). (E)-Oroidin isolated as free base (4a) was identified as the active component of the CHCl(3) extract. Compound 4a was a more potent PfFabI inhibitor (IC(50) 0.30 microg/ml=0.77 microM) than the (E)-oroidin TFA salt (4b), the active and major component of the aq MeOH extract (IC(50) 5.0 microg/ml). Enzyme kinetic studies showed 4a to be an uncompetitive PfFabI inhibitor (K(i): 0.4+/-0.2 and 0.8+/-0.2 microM with respect to substrate and cofactor). In addition, FAMA and FAMD (mainly consisting of methyl-branched fatty acids) inhibited FabI of Mycobacterium tuberculosis (MtFabI, IC(50)s 9.4 and 8.2 microg/ml, respectively) and Escherichia coli (EcFabI, IC(50)s 0.5 and 0.07 microg/ml, respectively). The majority of the compounds exhibited in vitro antiplasmodial, as well as trypanocidal and leishmanicidal activities without cytotoxicity towards mammalian cells. This study represents the first marine metabolites that inhibit FabI, a clinically relevant enzyme target from the FAS-II pathway of several pathogenic microorganisms.
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http://dx.doi.org/10.1016/j.bmc.2007.07.032DOI Listing
November 2007

Evidence from Raman spectroscopy that InhA, the mycobacterial enoyl reductase, modulates the conformation of the NADH cofactor to promote catalysis.

J Am Chem Soc 2007 May 2;129(20):6425-31. Epub 2007 May 2.

Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400, USA.

InhA, the enoyl reductase from Mycobacterium tuberculosis, catalyzes the NADH-dependent reduction of trans-2-enoyl-ACPs. In the present work, Raman spectroscopy has been used to identify catalytically relevant changes in the conformation of the nicotinamide ring that occur when NADH binds to InhA. For 4(S)-NADD, there is an 11 cm-1 decrease in the wavenumber of the C4-D stretching band (nuC-D) and a 50% decrease in the width of this band upon binding to InhA. While a similar reduction in line width is observed for the corresponding band arising from 4(R)-NADD, nuC-D for this isomer increases 34 cm-1 upon binding to InhA. These changes in nuC-D indicate that the nicotinamide ring adopts a bound conformation in which the 4(S)C-D bond is in a pseudoaxial orientation. Mutagenesis of F149, a conserved active site residue close to the cofactor, demonstrates that this enzyme-induced modulation in cofactor structure is directly linked to catalysis. In contrast to the wild-type enzyme, Raman spectra of NADD bound to F149A InhA resemble those of NADD in solution. Consequently, F149A is no longer able to optimally position the cofactor for hydride transfer, which correlates with the 30-fold decrease in kcat and 2-fold increase in D(V/KNADH) caused by this mutation. These studies thus substantiate the proposal that hydride transfer is promoted by pseudoaxial positioning of the NADH pro-4S bond, and indicate that catalysis of substrate reduction by InhA results, in part, from correct orientation of the cofactor in the ground state.
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http://dx.doi.org/10.1021/ja068219mDOI Listing
May 2007

High affinity InhA inhibitors with activity against drug-resistant strains of Mycobacterium tuberculosis.

ACS Chem Biol 2006 Feb;1(1):43-53

Department of Chemistry, SUNY Stony Brook, Stony Brook, New York 11794-3400, USA.

Novel chemotherapeutics for treating multidrug-resistant (MDR) strains of Mycobacterium tuberculosis (MTB) are required to combat the spread of tuberculosis, a disease that kills more than 2 million people annually. Using structure-based drug design, we have developed a series of alkyl diphenyl ethers that are uncompetitive inhibitors of InhA, the enoyl reductase enzyme in the MTB fatty acid biosynthesis pathway. The most potent compound has a Ki' value of 1 nM for InhA and MIC99 values of 2-3 microg mL(-1) (6-10 microM) for both drug-sensitive and drug-resistant strains of MTB. Overexpression of InhA in MTB results in a 9-12-fold increase in MIC99, consistent with the belief that these compounds target InhA within the cell. In addition, transcriptional response studies reveal that the alkyl diphenyl ethers fail to upregulate a putative efflux pump and aromatic dioxygenase, detoxification mechanisms that are triggered by the lead compound triclosan. These diphenyl ether-based InhA inhibitors do not require activation by the mycobacterial KatG enzyme, thereby circumventing the normal mechanism of resistance to the front line drug isoniazid (INH) and thus accounting for their activity against INH-resistant strains of MTB.
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http://dx.doi.org/10.1021/cb0500042DOI Listing
February 2006