A5076685416- HIV/AIDS drug development and treatment
- HIV Research and Treatment
- DNA and Nucleic Acid Chemistry
- Biochemical and Molecular Research
- Enzyme Structure and Function
- Viral Infections and Immunology Research
- RNA and protein synthesis mechanisms
- HIV/AIDS Research and Interventions
- Bacteriophages and microbial interactions
- Monoclonal and Polyclonal Antibodies Research
- Respiratory viral infections research
- Influenza Virus Research Studies
- Protein Structure and Dynamics
- Computational Drug Discovery Methods
- Viral gastroenteritis research and epidemiology
- Pneumocystis jirovecii pneumonia detection and treatment
- SARS-CoV-2 and COVID-19 Research
- Hepatitis C virus research
- Animal Disease Management and Epidemiology
- Glycosylation and Glycoproteins Research
- Click Chemistry and Applications
- Crystallization and Solubility Studies
- Cytomegalovirus and herpesvirus research
- Mycobacterium research and diagnosis
- interferon and immune responses
Rutgers, The State University of New Jersey
2016-2025
Diamond Light Source
2008-2025
University of Oxford
2025
AEgis Technologies (United States)
2023
Advanced Pharma
2003-2022
Rutgers Sexual and Reproductive Health and Rights
1999-2020
Roche Pharma AG (Germany)
2012
University of Pittsburgh
2006-2011
Quantitative BioSciences
2006-2011
Purdue University West Lafayette
1984-2010
The crystal structure of a ternary complex human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) heterodimer (p66/p51), 19-base/18-base double-stranded DNA template-primer, and monoclonal antibody Fab fragment has been determined at 3.0 A resolution. four individual subdomains RT that make up the polymerase domains p66 p51 are named fingers, palm, thumb, connection [Kohlstaedt, L. A., Wang, J., Friedman, J. M., Rice, P. A. & Steitz, T. (1992) Science 256, 1783-1790]....
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTIsolation and structure of bryostatin 1George R. Pettit, Cherry L. Herald, Dennis Doubek, Delbert Edward Arnold, Jon ClardyCite this: J. Am. Chem. Soc. 1982, 104, 24, 6846–6848Publication Date (Print):December 1, 1982Publication History Published online1 May 2002Published inissue 1 December 1982https://pubs.acs.org/doi/10.1021/ja00388a092https://doi.org/10.1021/ja00388a092research-articleACS PublicationsRequest reuse permissionsArticle...
Anti-AIDS drug candidate and non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC125-R165335 (etravirine) caused an initial drop in viral load similar to that observed with a five-drug combination naïve patients retains potency infected NNRTI-resistant HIV-1 variants. related anti-AIDS candidates can bind the enzyme RT multiple conformations thereby escape effects of drug-resistance mutations. Structural studies showed this other diarylpyrimidine (DAPY) analogues adapt changes...
Recent studies indicate that nitric oxide (NO) and guanosine 3',5'-cyclic monophosphate (cGMP) may inhibit the proliferation of vascular smooth muscle cells (SMC) in vitro. The purpose this study was to investigate mechanism NO- cGMP-dependent inhibition cultured rat aortic SMC. cytokine interleukin-1 beta (IL-1 beta) inhibited serum- platelet-derived growth factor-stimulated [3H]thymidine incorporation into DNA subcultured Incubation with IL-1 for 24 h markedly increased cGMP levels but not...
WIN 51711 and 52084 are structurally related, antiviral compounds that inhibit the replication of rhino (common cold) viruses related picornaviruses. They prevent pH-mediated uncoating viral RNA. The consist a 3-methylisoxazole group inserts itself into hydrophobic interior VP1 beta-barrel, connecting seven-membered aliphatic chain, 4-oxazolinylphenoxy (OP) covers entrance to an ion channel in floor "canyon." Viral disassembly may be inhibited by preventing collapse pocket or blocking flow...
A set of mutations [Ala-62-->Val(A62V), V75I, F77L, F116Y, and Q151M] in the polymerase domain reverse transcriptase (RT) human immunodeficiency virus type 1 (HIV-1) confers on a reduced sensitivity to multiple antiretroviral dideoxynucleosides has been seen HIV-1 variants isolated from patients receiving combination chemotherapy with 3'-azido-3'-deoxythymidine (AZT) plus 2',3'-dideoxycytidine (ddC) or 2',3'-dideoxyinosine (ddI). The IC50 values AZT, ddC, ddI, 2',3'-dideoxyguanosine,...
During transcription initiation, RNA polymerase (RNAP) binds and unwinds promoter DNA to form an RNAP-promoter open complex. We have determined crystal structures at 2.9 3.0 Å resolution of functional initiation complexes comprising Thermus thermophilus polymerase, σ(A), a fragment corresponding the bubble downstream double-stranded The show that σ recognizes -10 element discriminator through interactions include unstacking insertion into pockets three bases RNAP -4/+2 region pocket +2 base....
Isocitrate dehydrogenases (IDHs) catalyze the oxidative decarboxylation of isocitrate to alpha-ketoglutarate, and regulation enzymatic activity IDHs is crucial for their biological functions. Bacterial are reversibly regulated by phosphorylation a strictly conserved serine residue at active site. Eukaryotic NADP-dependent (NADP-IDHs) have been shown diverse important functions; however, regulatory mechanism remains unclear. Structural studies human cytosolic NADP-IDH (HcIDH) in complex with...
The structure of Mengo virus, a representative member the cardio picornaviruses, is substantially different from structures rhino- and polioviruses. virus was solved with use human rhinovirus 14 as an 8 Å resolution structural approximation. Phase information then extended to 3 by icosahedral symmetry. This procedure gives promise that many other also can be determined without isomorphous replacement technique. Although organization major capsid proteins VP1, VP2, VP3 essentially same in...
TMC278 is a diarylpyrimidine (DAPY) nonnucleoside reverse transcriptase inhibitor (NNRTI) that highly effective in treating wild-type and drug-resistant HIV-1 infections clinical trials at relatively low doses ( approximately 25-75 mg/day). We have determined the structure of RT complexed with 1.8 A resolution, using an crystal form engineered by systematic mutagenesis. This high-resolution reveals cyanovinyl group positioned hydrophobic tunnel connecting NNRTI-binding pocket to nucleic...
Abstract The LINE-1 (L1) retrotransposon is an ancient genetic parasite that has written around one-third of the human genome through a ‘copy and paste’ mechanism catalysed by its multifunctional enzyme, open reading frame 2 protein (ORF2p) 1 . ORF2p reverse transcriptase (RT) endonuclease activities have been implicated in pathophysiology cancer 2,3 , autoimmunity 4,5 ageing 6,7 making potential therapeutic target. However, lack structural mechanistic knowledge hampered efforts to...
The emergence of SARS-CoV-2 variants and drug-resistant mutants calls for additional oral antivirals. papain-like protease (PL pro ) is a promising but challenging drug target. We designed synthesized 85 noncovalent PL inhibitors that bind to recently discovered ubiquitin binding site the known BL2 groove pocket near S4 subsite. Leads inhibited with inhibitory constant K i values from 13.2 88.2 nanomolar. co-crystal structures eight leads revealed their interaction modes. in vivo lead...
An important component of triple-drug anti-AIDS therapy is 2′,3′-dideoxy-3′-thiacytidine (3TC, lamivudine). Single mutations at residue 184 the reverse transcriptase (RT) in HIV cause high-level resistance to 3TC and contribute failure combination therapy. We have determined crystal structures 3TC-resistant mutant HIV-1 RT (M184I) both presence absence a DNA/DNA template-primer. In DNA substrate, wild-type are very similar. However, comparison M184I with without reveals repositioning...
ABSTRACT Success in treating hepatitis B virus (HBV) infection with nucleoside analog drugs like lamivudine is limited by the emergence of drug-resistant viral strains upon prolonged therapy. The predominant resistance mutations HBV-infected patients are Met552IIe and Met552Val (Met552Ile/Val), frequently association a second mutation, Leu528Met. effects Leu528Met, Met552Ile, on binding HBV polymerase inhibitors natural substrate dCTP were evaluated using an vitro assay. Susceptibility to...
ABSTRACT Therapy of chronic hepatitis B virus (HBV) infection with the polymerase inhibitor lamivudine frequently is associated emergence viral resistance. Genotypic changes in YMDD motif (reverse transcriptase [rt] mutations rtM204V/I) conferred resistance to as well reducing vitro replication efficiency HBV. A second mutation, rtL180M, was previously reported partially restore fitness augment drug vitro. Here we report functional characterization a third mutation (rtV173L) and famciclovir....