A5055478360- HIV/AIDS drug development and treatment
- HIV Research and Treatment
- Pneumocystis jirovecii pneumonia detection and treatment
- Biochemical and Molecular Research
- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- RNA and protein synthesis mechanisms
- RNA modifications and cancer
- SARS-CoV-2 and COVID-19 Research
- HIV/AIDS Research and Interventions
- Click Chemistry and Applications
- RNA Research and Splicing
- Computational Drug Discovery Methods
- Synthesis and Reactivity of Heterocycles
- Chemical Synthesis and Analysis
- Protein Structure and Dynamics
- Cellular transport and secretion
- HIV-related health complications and treatments
- Enzyme Structure and Function
- Lipid Membrane Structure and Behavior
- Iron Metabolism and Disorders
- Parasitic Infections and Diagnostics
- Molecular Biology Techniques and Applications
- Fluorine in Organic Chemistry
- Advanced Materials and Mechanics
Yale University
2015-2024
University of New Haven
2014
Université du Québec à Montréal
2004-2014
Institute of Molecular Biology and Biophysics
2009
University of Guelph
2002-2008
Starting from our previous finding of 14 known drugs as inhibitors the main protease (Mpro) SARS-CoV-2, virus responsible for COVID-19, we have redesigned weak hit perampanel to yield multiple noncovalent, nonpeptidic with ca. 20 nM IC50 values in a kinetic assay. Free-energy perturbation (FEP) calculations Mpro-ligand complexes provided valuable guidance on beneficial modifications that rapidly delivered potent analogues. The design efforts were confirmed and augmented by determination...
A 5-μM docking hit has been optimized to an extraordinarily potent (55 pM) non-nucleoside inhibitor of HIV reverse transcriptase. Use free energy perturbation (FEP) calculations predict relative energies binding aided the optimizations by identifying optimal substitution patterns for phenyl rings and a linker. The most resultant catechol diethers feature terminal uracil cyanovinylphenyl groups. halogen bond with Pro95 likely contributes extreme potency compound 42. In addition, several...
Members of the catechol diether class are highly potent non-nucleoside inhibitors HIV-1 reverse transcriptase (NNRTIs). The most active compounds yield EC50 values below 0.5 nM in assays using human T-cells infected by wild-type HIV-1. However, these such as rilpivirine, recently FDA-approved NNRTI, bear a cyanovinylphenyl (CVP) group. This is an uncommon substructure drugs that gives reactivity concerns. In present work, computer simulations were used to design bicyclic replacements for CVP...
As the SARS-CoV-2 virus continues to spread and mutate, it remains important focus not only on preventing through vaccination but also treating infection with direct-acting antivirals (DAA). The approval of Paxlovid, a main protease (M pro ) DAA, has been significant for treatment patients. A limitation this however, is that antiviral component, nirmatrelvir, rapidly metabolized requires inclusion CYP450 3A4 metabolic inhibitor, ritonavir, boost levels active drug. Serious drug–drug...
Non-covalent inhibitors of the main protease (Mpro) SARS-CoV-2 having a pyridinone core were previously reported with IC50 values as low 0.018 μM for inhibition enzymatic activity and EC50 0.8 viral replication in Vero E6 cells. The series has now been further advanced by consideration placement substituted five-membered-ring heterocycles S4 pocket Mpro N-methylation uracil ring. Free energy perturbation calculations provided guidance on choice heterocycles, protein crystallography confirmed...
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) that interfere with the replication of human immunodeficiency virus (HIV) are being pursued guidance from molecular modeling including free-energy perturbation (FEP) calculations for protein-inhibitor binding affinities. The previously reported pyrimidinylphenylamine 1 and its chloro analogue 2 potent anti-HIV agents; they inhibit wild-type HIV-1 in infected T-cells EC(50) values 10 nM, respectively. However, show no activity against...
Cysteine plays a number of important functional and structural roles in nature, often the realm catalysis. Herein, we present an example cysteine-promoted Rauhut-Currier reaction for potentially biomimetic synthesis Sch-642305 related analogs. In this key step discuss interesting new discoveries importance substrate-catalyst recognition, as well cysteine's features. Also, investigate activity four analogs HIV-infected T-cells.
The development of novel non-nucleoside inhibitors (NNRTIs) with activity against variants HIV reverse transcriptase (RT) is crucial for overcoming treatment failure. NNRTIs bind in an allosteric pocket RT ∼10 Å away from the active site. Earlier analogues catechol diether compound series have picomolar strains wild-type but lose potency single Y181C and double K103N/Y181C mutations. As guided by structure-based computational studies, removal 5-Cl substitution 1 on aryl ring system led to a...
Significance HIV-1 reverse transcriptase (RT) has been the prime target for anti-HIV chemotherapy; however, its rapid mutation often generates drug resistance. Prominent variant strains of that lead to treatment failure with nonnucleoside RT inhibitors (NNRTIs) bear Tyr181Cys in RT. Based on our previous discovery and crystallography potent noncovalent NNRTIs, new compounds were designed incorporation chemical warheads intended modify covalently Cys181. Here we report success strategy,...
Catechol diethers that incorporate a 6-cyano-1-naphthyl substituent have been explored as non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs). Promising compounds are reported show midpicomolar activity against the wild-type virus and sub-20 nM viral variants bearing Tyr181Cys Lys103Asn mutations in HIV-RT. An X-ray crystal structure at 2.49 Å resolution is also for key compound 6e with
Most species, such as humans, have monofunctional forms of thymidylate synthase (TS) and dihydrofolate reductase (DHFR) that are key folate metabolism enzymes making critical components required for DNA synthesis. In contrast, several parasitic protozoa, including Toxoplasma gondii, contain a unique bifunctional synthase-dihydrofolate (TS-DHFR) having the catalytic activities contained on single polypeptide chain. The prevalence T. gondii infections across world, especially those...
Significance Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are essential components of highly active antiretroviral therapy; however, concerns about poor pharmacological properties, dose restriction because toxicity, and drug resistance have limited treatment options. Our computational structure-guided design studies for lead optimization transformed a 5 µM virtual screening hit into class NNRTIs with remarkable potency, safety, profile, properties. We report representative,...
Catechol diethers that incorporate a 7-cyano-2-naphthyl substituent are reported as non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs). Many the compounds have 1-10 nM potencies toward wild-type HIV-1. An interesting conformational effect allows two unique conformers for naphthyl group in complexes with HIV-RT. X-ray crystal structures 4a and 4f illustrate alternatives.
Covalent inhibitors of wild-type HIV-1 reverse transcriptase (CRTIs) are reported. Three compounds derived from catechol diether non-nucleoside (NNRTIs) with addition a fluorosulfate warhead demonstrated to covalently modify Tyr181 HIV-RT. X-ray crystal structures for complexes the CRTIs enzyme provided, which fully demonstrate covalent attachment, and confirmation is provided by appropriate mass shifts in ESI-TOF spectra. The three six noncovalent analogues found be potent both IC
Catechol diether compounds have nanomolar antiviral and enzymatic activity against HIV with reverse transcriptase (RT) variants containing K101P, a mutation that confers high-level resistance to FDA-approved non-nucleoside inhibitors efavirenz rilpivirine. Kinetic data suggests RT (K101P) are as catalytically fit wild-type thus can potentially increase in the viral population more regimens include or Comparison of structures new crystal structure complex leading compound confirms K101P is...
DEAD-box RNA helicase Dbp4 is required for 18S rRNA synthesis: cellular depletion of impairs the early cleavage reactions pre-rRNA and causes U14 small nucleolar (snoRNA) to remain associated with pre-rRNA. Immunoprecipitation experiments (IPs) carried out whole-cell extracts (WCEs) revealed that hemagglutinin (HA)-tagged U3 snoRNA but not snoRNA. IPs WCEs also showed association U3-specific protein Mpp10, which suggests interacts functionally active RNP; this particle, called small-subunit...
Here we report on the structure-based optimization of antibody-recruiting molecules targeting HIV gp120 (ARM-H). These studies have leveraged a combination medicinal chemistry, biochemical and cellular assay analysis, computation. Our findings afforded an optimized analog ARM-H, which is ~1000 fold more potent in gp120-binding MT-2 antiviral assays than our previously reported derivative. Furthermore, computational taken together with experimental data, provides evidence that azaindole-...