14,990 results match your criteria potency inhibitor

A novel highly potent inhibitor of TMPRSS2-like proteases blocks SARS-CoV-2 variants of concern and is broadly protective against infection and mortality in mice.

bioRxiv 2021 May 4. Epub 2021 May 4.

The COVID-19 pandemic caused by the SARS-CoV-2 virus remains a global public health crisis. Although widespread vaccination campaigns are underway, their efficacy is reduced against emerging variants of concern (VOCs) . Development of host-directed therapeutics and prophylactics could limit such resistance and offer urgently needed protection against VOCs . Read More

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Design, synthesis and biological evaluation of imidazopyridazine derivatives containing isoquinoline group as potent MNK1/2 inhibitors.

Bioorg Med Chem 2021 May 2;40:116186. Epub 2021 May 2.

Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China. Electronic address:

Mitogen-activated protein kinase (MAPK)-interacting kinases (MNKs) are located at the meeting-point of ERK and p38 MAPK signaling pathways, which can phosphorylate eukaryotic translation initiation factor 4E (eIF4E) at the conserved serine 209 exclusively. MNKs modulate the translation of mRNA involved in tumor-associated signaling pathways. Consequently, selective inhibitors of MNK1/2 could reduce the level of phosphorylated eIF4E. Read More

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Phosphatidylinositol 3-kinase (PI3K) inhibitors: a recent update on inhibitor design and clinical trials (2016-2020).

Expert Opin Ther Pat 2021 May 10. Epub 2021 May 10.

DSC 362, Department of Chemistry, The University of Nebraska at Omaha, 6001 Dodge Street, Omaha, Nebraska 68182, USA.

Introduction: The phosphatidylinositol 3-kinase/protein kinase-B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway plays a central role in regulating cell growth and proliferation and thus have been considered as effective anticancer drug targets. Many PI3K inhibitors have been developed and progressed to various stages of clinical trials and some even have been approved in recent years by the regulatory agency as anticancer treatment. In this review, we discuss the drug design and clinical development of PI3K inhibitors in the past four years. Read More

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Inhibition of Plasmodium falciparum Lysyl-tRNA synthetase via a piperidine-ring scaffold inspired Cladosporin analogues.

Chembiochem 2021 May 9. Epub 2021 May 9.

National Institute of Malaria Research, Director, Sector 8 Dwarka, Dwarka, New Delhi, Delhi 110077, 110077, delhi, INDIA.

Plasmodium falciparum lysyl tRNA synthetase ( Pf KRS) represent a promising therapeutic anti-malarial target. Cladosporin, a tool compound was identified as a selective and potent PfKRS inhibitor but lacks metabolic stability. Here, we report chemical synthesis, biological evaluation and structural characterization of analogues where the tetrahydropyran (THP) frame of cladosporin is replaced with the piperidine ring bearing functional group variations. Read More

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Novel benzenesulfonamides aryl and arylsulfone conjugates adopting tail/dual tail approaches: Synthesis, carbonic anhydrase inhibitory activity and molecular modeling studies.

Eur J Med Chem 2021 Apr 27;221:113486. Epub 2021 Apr 27.

Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy. Electronic address:

New series of benzenesulfonamide and benzoic acid derivatives were designed and synthesized using tail/dual tail approach to improve potency and selectivity as carbonic anhydrase inhibitors. The synthesized compounds evaluated as CAIs against isoforms hCA I, II, IV and IX with acetazolamide (AAZ) as standard inhibitor. The benzenesulfonamide derivatives 7a-d, 8a-h, 12a-c, 13a and 15a-c showed moderate to potent inhibitory activity with selectivity toward isoform hCA II, especially, compound 13a with (K = 7. Read More

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Downregulated expression of intestinal P-glycoprotein in rats with cisplatin-induced acute kidney injury causes amplification of its transport capacity to maintain "gatekeeper" function.

Toxicol Appl Pharmacol 2021 May 6:115570. Epub 2021 May 6.

Department of Pharmaceutics, School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Japan. Electronic address:

The expression of transporters on the apical and basal membranes of renal proximal tubular cells are down- or upregulated to various extents under cisplatin (CDDP)-induced acute kidney injury (AKI). However, little is known about the changes in transporters in tissues other than the kidney under CDDP-induced AKI. This study aimed to investigate the modulation of the expression/function of intestinal efflux transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp), in CDDP-induced AKI rats. Read More

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Discovery of a novel highly potent broad-spectrum heterocyclic chemical series of arenavirus cell entry inhibitors.

Bioorg Med Chem Lett 2021 Jun 5;41:127983. Epub 2021 May 5.

Arisan Therapeutics, 11189 Sorrento Valley Rd, Suite 104, San Diego 92121, CA, United States. Electronic address:

We identified and explored the structure-activity relationship (SAR) of a novel heterocyclic chemical series of arenavirus cell entry inhibitors. Optimized lead compounds, including diphenyl-substituted imidazo[1,2-a]pyridines, benzimidazoles, and benzotriazoles exhibited low to sub-nanomolar potency against both pseudotyped and infectious Old and New World arenaviruses, attractive metabolic stability in human and most nonhuman liver microsomes as well as a lack of hERG K + channel or CYP enzyme inhibition. Moreover, the straightforward synthesis of several lead compounds (e. Read More

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OSU-03012 Disrupts Akt Signaling and Prevents Endometrial Carcinoma Progression in vitro and in vivo.

Drug Des Devel Ther 2021 30;15:1797-1810. Epub 2021 Apr 30.

Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China.

Purpose: OSU-03012 is a celecoxib derivative lacking cyclooxygenase-2 inhibitory activity and a potent PDK1 inhibitor which has been shown to inhibit tumor growth in various ways. However, the role of OSU-03012 in endometrial carcinoma (EC) in which the PI3K/Akt signaling pathway highly activated has not been studied. Here, we determined the potency of OSU-03012 in suppressing EC progression in vitro and in vivo, and studied the underlined mechanisms. Read More

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Design, synthesis, and biological evaluation of novel dual inhibitors targeting lysine specific demethylase 1 (LSD1) and histone deacetylases (HDAC) for treatment of gastric cancer.

Eur J Med Chem 2021 Apr 25;220:113453. Epub 2021 Apr 25.

School of Pharmacy, Xinxiang Medical University, Xinxiang, Henan, 453003, China. Electronic address:

LSD1 and HDAC are physical and functional related to each other in various human cancers and simultaneous pharmacological inhibition of LSD1 and HDAC exerts synergistic anti-cancer effects. In this work, a series of novel LSD1/HDAC bifunctional inhibitors with a styrylpyridine skeleton were designed and synthesized based on our previously reported LSD1 inhibitors. The representative compounds 5d and 5m showed potent activity against LSD1 and HDAC at both molecular and cellular level and displayed high selectivity against MAO-A/B. Read More

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Discovery of Novel, Potent Inhibitors of Hydroxy Acid Oxidase 1 (HAO1) Using DNA-Encoded Chemical Library Screening.

J Med Chem 2021 May 6. Epub 2021 May 6.

X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States.

Inhibition of hydroxy acid oxidase 1 (HAO1) is a strategy to mitigate the accumulation of toxic oxalate that results from reduced activity of alanine-glyoxylate aminotransferase (AGXT) in primary hyperoxaluria 1 (PH1) patients. DNA-Encoded Chemical Library (DECL) screening provided two novel chemical series of potent HAO1 inhibitors, represented by compounds -. Compound was further optimized via various structure-activity relationship (SAR) exploration methods to , a compound with improved potency and absorption, distribution, metabolism, and excretion (ADME)/pharmacokinetic (PK) properties. Read More

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Bioactive stigmastadienone from Isodon rugosus as potential anticholinesterase, α-glucosidase and COX/LOX inhibitor: In-vitro and molecular docking studies.

Steroids 2021 May 1;172:108857. Epub 2021 May 1.

Department of Pharmaceutical Chemistry, College of Pharmacy, Najran University, Najran, Saudi Arabia.

Natural product is a well-known source of bioactive compounds. Herein, a steroidal compound stigmasta-7,22-diene-3-one (stigmastadienone) has been isolated from Isodon rugosus. The potency of isolated compound has been tested for several in-vitro targets. Read More

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mRNA Delivery of a Bispecific Single-Domain Antibody to Polarize Tumor-Associated Macrophages and Synergize Immunotherapy against Liver Malignancies.

Adv Mater 2021 May 4:e2007603. Epub 2021 May 4.

Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.

Liver malignancies are among the tumor types that are resistant to immune checkpoint inhibition therapy. Tumor-associated macrophages (TAMs) are highly enriched and play a major role in inducing immunosuppression in liver malignancies. Herein, CCL2 and CCL5 are screened as two major chemokines responsible for attracting TAM infiltration and inducing their polarization toward cancer-promoting M2-phenotype. Read More

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Design, synthesis and biological evaluations of a series of Pyrido[1,2-a]pyrimidinone derivatives as novel selective FGFR inhibitors.

Eur J Med Chem 2021 Apr 26;220:113499. Epub 2021 Apr 26.

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, And Collaborative Innovation Center for Biotherapy, 17#3rd Section, Ren Min South Road, Chengdu, 610041, China. Electronic address:

Aberrant signaling of fibroblast growth factor receptors (FGFRs) has been identified as a driver of tumorigenesis and the development of many solid tumors, making FGFRs a compelling target for anticancer therapy. Herein, we describe the design and synthesis of pyrido[1,2-a]pyrimidinone derivatives as potent FGFR inhibitors. Examination of structure-activity relationships and preliminary assessment identified 23d as a novel FGFR inhibitor that displayed excellent potency in vitro. Read More

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New Quinolinone O-GlcNAc Transferase Inhibitors Based on Fragment Growth.

Front Chem 2021 14;9:666122. Epub 2021 Apr 14.

The Chair of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia.

O-GlcNAcylation is an important post-translational and metabolic process in cells that must be carefully regulated. O-GlcNAc transferase (OGT) is ubiquitously present in cells and is the only enzyme that catalyzes the transfer of O-GlcNAc to proteins. OGT is a promising target in various pathologies such as cancer, immune system diseases, or nervous impairment. Read More

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Design and biological evaluation of cinnamic and phenylpropionic amide derivatives as novel dual inhibitors of HIV-1 protease and reverse transcriptase.

Eur J Med Chem 2021 Apr 24;220:113498. Epub 2021 Apr 24.

Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China. Electronic address:

Upon the basis of both possible ligand-binding site interactions and the uniformity of key residues in active sites, a novel class of HIV-1 PR/RT dual inhibitors was designed and evaluated. Cinnamic acids or phenylpropionic acids with more flexible chain and smaller steric hindrance were introduced into the inhibitors, giving rise to significant improvement in HIV-1 RT inhibitory activity by one or two orders of magnitude, with comparable or even improved potency against PR at the same time, compared with coumarin anologues in our previous studies. Among these inhibitors, 38d displayed a 19-fold improvement in anti-PR activity with IC value of 0. Read More

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The effect of caspase-9 in the differentiation of SH-SY5Y cells.

Eur J Pharmacol 2021 Apr 29:174138. Epub 2021 Apr 29.

Hematology, Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran; Cell Therapy and Hematopoietic Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

Neuroblastoma is the most common solid malignant tumor in infants and young children. Its origin is the incompletely committed precursor cells from the autonomic nervous system. Neuroblastoma cells are multipotent cells with a high potency of differentiation into the neural cell types. Read More

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Design, synthesis and biological evaluation of novel estrone phosphonates as high affinity organic anion-transporting polypeptide 2B1 (OATP2B1) inhibitors.

Bioorg Chem 2021 Apr 20;112:104914. Epub 2021 Apr 20.

Department of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary. Electronic address:

Organic anion-transporting polypeptide 2B1 (OATP2B1) is a multispecific membrane transporter mediating the cellular uptake of various exo- and endobiotics, including drugs and steroid hormones. Increased uptake of steroid hormones by OATP2B1 may increase tumor proliferation. Therefore, understanding OATP2B1's substrate/inhibitor recognition and inhibition of its function, e. Read More

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Discovery of potent and selective reversible Bruton's tyrosine kinase inhibitors.

Bioorg Med Chem 2021 Apr 20;40:116163. Epub 2021 Apr 20.

EMD Serono Research & Development Institute, 45A Middlesex Turnpike, Billerica, MA 01821, USA(1).

Bruton's tyrosine kinase (BTK) is a cytoplasmic, non-receptor tyrosine kinase member of the TEC family of tyrosine kinases. Pre-clinical and clinical data have shown that targeting BTK can be used for the treatment for B-cell disorders. Here we disclose the discovery of a novel imidazo[4,5-b]pyridine series of potent, selective reversible BTK inhibitors through a rational design approach. Read More

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J Pharmacol Exp Ther 2021 Apr 30. Epub 2021 Apr 30.

Gavin Herbert Eye Institute, Dept. of Ophthalmology, University of California, Irvine, United States

CB-5083 is an inhibitor of p97/valosin-containing protein (VCP), for which Phase I trials for cancer were terminated due to adverse effects on vision, such as photophobia and dyschromatopsia. Lower dose CB-5083 could combat inclusion body myopathy with early-onset Paget disease; and frontotemporal dementia or multisystem proteinopathy, caused by gain-of-function mutations in VCP. We hypothesized that the visual impairment in the cancer trial was due to CB-5083's inhibition of phosphodiesterase-6 (PDE6), which mediates signal transduction in photoreceptors. Read More

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Aspirin-free antiplatelet regimens after PCI: insights from the GLOBAL LEADERS trial and beyond.

Eur Heart J Cardiovasc Pharmacother 2021 Apr 30. Epub 2021 Apr 30.

East Lancashire Hospitals NHS Trust, Blackburn, Lancashire, United Kingdom.

Historically, aspirin has been the primary treatment for the prevention of ischemic events in patients with coronary artery disease. For patients undergoing percutaneous coronary intervention (PCI) standard treatment has been 12-months of dual anti-platelet therapy (DAPT) with aspirin and clopidogrel, followed by aspirin monotherapy; however, DAPT is undeniably associated with an increased risk of bleeding. For over a decade novel P2Y12 inhibitors, which have increased specificity, potency and efficacy have been available, prompting studies which have tested whether these newer agents can be used in aspirin-free anti-platelet regimens to augment clinical benefits in patients post-PCI. Read More

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EBNA1 inhibitors have potent and selective antitumor activity in xenograft models of Epstein-Barr virus-associated gastric cancer.

Gastric Cancer 2021 Apr 30. Epub 2021 Apr 30.

The Wistar Institute, 3601 Spruce Street, Philadelphia, PA, 19104, USA.

Background And Aims: Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) is the most common EBV-associated cancer and accounts for ~ 10% of all gastric cancers (GC). Epstein-Barr virus nuclear antigen 1 (EBNA1), which is critical for the replication and maintenance of the EBV latent genome, is consistently expressed in all EBVaGC tumors. We previously developed small molecule inhibitors of EBNA1. Read More

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Protamine Sulfate Neutralization Profile of Various Dosages of Bovine, Ovine and Porcine UFHs and Their Depolymerized Derivatives in Non-Human Primates.

Clin Appl Thromb Hemost 2021 Jan-Dec;27:10760296211005544

Cardiovascular Research Institute, 2456Loyola University Chicago, Health Sciences Division, Maywood, IL, USA.

Introduction: Currently used unfractionated heparins (UFHs) and low molecular weight heparins (LMWHs) are derived from porcine intestinal mucosa. However, heparins have also been manufactured from tissues of other mammalian species such as cow (Bovine) and sheep (Ovine). Protamine sulphate (PS) is an effective inhibitor of heparin and is used clinically to neutralize both LMWH and UFH. Read More

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Pre-Senescence Induction in Hepatoma Cells Favors Hepatitis C Virus Replication and Can Be Used in Exploring Antiviral Potential of Histone Deacetylase Inhibitors.

Int J Mol Sci 2021 Apr 27;22(9). Epub 2021 Apr 27.

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia.

Recent evidence suggests that fibrotic liver injury in patients with chronic hepatitis C correlates with cellular senescence in damaged liver tissue. However, it is still unclear how senescence can affect replication of the hepatitis C virus (HCV). In this work, we report that an inhibitor of cyclin-dependent kinases 4/6, palbociclib, not only induced in hepatoma cells a pre-senescent cellular phenotype, including G1 arrest in the cell cycle, but also accelerated viral replicon multiplication. Read More

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Stability of Imprinting and Differentiation Capacity in Naïve Human Cells Induced by Chemical Inhibition of CDK8 and CDK19.

Cells 2021 Apr 12;10(4). Epub 2021 Apr 12.

Cellular Plasticity and Disease Group, Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain.

Pluripotent stem cells can be stabilized in vitro at different developmental states by the use of specific chemicals and soluble factors. The naïve and primed states are the best characterized pluripotency states. Naïve pluripotent stem cells (PSCs) correspond to the early pre-implantation blastocyst and, in mice, constitute the optimal starting state for subsequent developmental applications. Read More

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PK/PD Modeling of the PDE7 Inhibitor-GRMS-55 in a Mouse Model of Autoimmune Hepatitis.

Pharmaceutics 2021 Apr 21;13(5). Epub 2021 Apr 21.

Department of Pharmacokinetics and Physical Pharmacy, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.

This study aimed to assess the efficacy and explore the mechanisms of action of a potent phosphodiesterase (PDE)7A and a moderate PDE4B inhibitor GRMS-55 in a mouse model of autoimmune hepatitis (AIH). The concentrations of GRMS-55 and relevant biomarkers were measured in the serum of BALB/c mice with concanavalin A (ConA)-induced hepatitis administered with GRMS-55 at two dose levels. A semi-mechanistic PK/PD/disease progression model describing the time courses of measured biomarkers was developed. Read More

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Rutin Is a Low Micromolar Inhibitor of SARS-CoV-2 Main Protease 3CLpro: Implications for Drug Design of Quercetin Analogs.

Biomedicines 2021 Apr 2;9(4). Epub 2021 Apr 2.

Institute for Biocomputation and Physics of Complex Systems (BIFI), Joint Units IQFR-CSIC-BIFI, and GBsC-CSIC-BIFI, University of Zaragoza, 50018 Zaragoza, Spain.

The pandemic, due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has stimulated the search for antivirals to tackle COVID-19 infection. Molecules with known pharmacokinetics and already approved for human use have been demonstrated or predicted to be suitable to be used either directly or as a base for a scaffold-based drug design. Among these substances, quercetin is known to be a potent in vitro inhibitor of 3CLpro, the SARS-CoV-2 main protease. Read More

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Design and Synthesis of a Novel PLK1 Inhibitor Scaffold Using a Hybridized 3D-QSAR Model.

Int J Mol Sci 2021 Apr 8;22(8). Epub 2021 Apr 8.

College of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan 426-791, Korea.

Polo-like kinase 1 (PLK1) plays an important role in cell cycle progression and proliferation in cancer cells. PLK1 also contributes to anticancer drug resistance and is a valuable target in anticancer therapeutics. To identify additional effective PLK1 inhibitors, we performed QSAR studies of two series of known PLK1 inhibitors and proposed a new structure based on a hybridized 3D-QSAR model. Read More

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Novel and Potent Small Molecules against Melanoma Harboring BRAF Class I/II/III Mutants for Overcoming Drug Resistance.

Int J Mol Sci 2021 Apr 6;22(7). Epub 2021 Apr 6.

KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Korea.

Melanoma accounts for the majority of skin cancer deaths. About 50% of all melanomas are associated with BRAF mutations. BRAF mutations are classified into three classes with regard to dependency on RAF dimerization and RAS signaling. Read More

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In Silico Mining of Terpenes from Red-Sea Invertebrates for SARS-CoV-2 Main Protease (M) Inhibitors.

Molecules 2021 Apr 5;26(7). Epub 2021 Apr 5.

Chemistry of Medicinal Plants Department, National Research Centre, 33 El-Bohouth St., Dokki, Giza 12622, Egypt.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent for the COVID-19 pandemic, which generated more than 1.82 million deaths in 2020 alone, in addition to 83.8 million infections. Read More

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Binding and Action of Triphenylphosphonium Analog of Chloramphenicol upon the Bacterial Ribosome.

Antibiotics (Basel) 2021 Apr 5;10(4). Epub 2021 Apr 5.

Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL 60607, USA.

Chloramphenicol (CHL) is a ribosome-targeting antibiotic that binds to the peptidyl transferase center (PTC) of the bacterial ribosome and inhibits peptide bond formation. As an approach for modifying and potentially improving the properties of this inhibitor, we explored ribosome binding and inhibitory properties of a semi-synthetic triphenylphosphonium analog of CHL-CAM-C4-TPP. Our data demonstrate that this compound exhibits a ~5-fold stronger affinity for the bacterial ribosome and higher potency as an in vitro protein synthesis inhibitor compared to CHL. Read More

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