A5034051890- HIV/AIDS drug development and treatment
- HIV Research and Treatment
- Hepatitis C virus research
- Biochemical and Molecular Research
- Bacteriophages and microbial interactions
- HIV/AIDS Research and Interventions
- Hepatitis B Virus Studies
- DNA and Nucleic Acid Chemistry
- Synthesis and Characterization of Heterocyclic Compounds
- Chemical Synthesis and Analysis
- Monoclonal and Polyclonal Antibodies Research
- Pneumocystis jirovecii pneumonia detection and treatment
- Protein Structure and Dynamics
- Synthesis and biological activity
- RNA and protein synthesis mechanisms
- Mass Spectrometry Techniques and Applications
- Analytical chemistry methods development
- Metabolomics and Mass Spectrometry Studies
- Ion-surface interactions and analysis
- T-cell and Retrovirus Studies
- Cytomegalovirus and herpesvirus research
- Galectins and Cancer Biology
- Supramolecular Chemistry and Complexes
- Superconducting Materials and Applications
- Protein purification and stability
Children's Healthcare of Atlanta
2021-2025
Emory University
2018-2025
University of Missouri
2011-2024
Candy’s Place
2014
Baoshan College
2010
Piaggio (Italy)
2009
Retroviral capsids in their native form Capsid proteins of retroviruses protective lattices around viral RNA molecules. The precise molecular details how individual, full-length capsid assemble to shield the genome; however, are not well understood. Obal et al. and Gres now report high resolution crystal structures full length from Bovine Leukemia Virus HIV-1, respectively. two studies complement each other reveal dynamic nature protein assembly individual interact lattice. findings may have...
Coronavirus Disease 2019 (COVID-19) is a deadly emerging infectious disease caused by Severe Acute Respiratory Syndrome 2 (SARS-CoV-2). Because SARS-CoV-2 easily transmitted through the air and has relatively long incubation time, COVID-19 rapidly developed into global pandemic. As there are no antiviral agents for prevention treatment of this severe pathogen except remdesivir, development therapies to treat infected individuals remains highly urgent. Here, we showed that baicalein baicalin...
Reverse transcriptase (RT) associated ribonuclease H (RNase H) remains the only virally encoded enzymatic function not targeted by current chemotherapy against human immunodeficiency virus (HIV). Although numerous chemotypes have been reported to inhibit HIV RNase biochemically, few show significant antiviral activity HIV. We report herein design, synthesis, and biological evaluations of a novel variant 2-hydroxyisoquinoline-1,3-dione (HID) scaffold featuring crucial C-6 benzyl or...
4′-Ethynyl-2-fluoro-2′-deoxyadenosine (EFdA) is a nucleoside analog that, unlike approved anti-human immunodeficiency virus type 1 (HIV-1) reverse transcriptase inhibitors, has 3′-OH and exhibits remarkable potency against wild-type drug-resistant HIVs. EFdA triphosphate (EFdA-TP) unique among inhibitors because it inhibits HIV-1 (RT) with multiple mechanisms. (a) EFdA-TP can block RT as translocation-defective inhibitor that dramatically slows DNA synthesis, acting de facto immediate chain...
Significance 4′-Ethynyl-2-fluoro-2′-deoxyadenosine (EFdA), a potent antiviral with an unusually long half-life, is currently in phase I clinical trials. It inhibits reverse transcriptase (RT) through mechanism of action different from all approved anti-HIV drugs: After incorporation the nascent DNA chain, it suppresses rate viral replication by diminishing RT translocation on nucleic acid substrate. Here, we present four crystal structures various inhibition intermediates. The provide...
HIV-1 Reverse Transcriptase (HIV-1 RT) has been the target of numerous approved anti-AIDS drugs that are key components Highly Active Anti-Retroviral Therapies (HAART). It remains extensive structural studies continue unabated for almost twenty years. The crystal structures wild-type or drug-resistant mutant HIV RTs in unliganded form complex with substrates and/or have offered valuable glimpses into enzyme's folding and its interactions DNA dNTP substrates, as well nucleos(t)ide reverse...
Targeting the clinically unvalidated reverse transcriptase (RT) associated ribonuclease H (RNase H) for human immunodeficiency virus (HIV) drug discovery generally entails chemotypes capable of chelating two divalent metal ions in RNase active site. The hydroxypyridonecarboxylic acid scaffold has been implicated inhibiting homologous HIV integrase (IN) and influenza endonuclease via chelation. We report herein design, synthesis, biological evaluations a novel variant featuring crucial N-1...
Native mass spectrometry (nMS) is an increasingly popular technique for studying intact protein quaternary structure. When coupled with ion mobility, which separates ions based on their size, charge, and shape, it provides additional structural information the complex of interest. We present here data from a novel prototype TIMS (trapped mobility spectrometry)-quadrupole-SID (surface-induced dissociation)-time flight, TIMS-Q-SID-TOF, instrument nMS. The modifications include changing...
Genetic mutations in the phosphatase PTPN11 (SHP2) are associated with childhood leukemias. These cause hyperactivation of SHP2 due to disruption autoinhibitory conformation. By targeting activation-associated protein conformational change, we have identified an inhibitor (E)-1-(1-(5-(3-(2,4-dichlorophenyl)acryloyl)-2-ethoxy-4-hydroxybenzyl)-1,2,5,6-tetrahydropyridin-3-yl)-1H-benzo[d]imidazol-2(3H)-one (LY6, 1) using computer-aided drug design database screening combined cell-based assays....
Human immunodeficiency virus (HIV) reverse transcriptase (RT) associated ribonuclease H (RNase H) remains an unvalidated antiviral target. A major challenge of specifically targeting HIV RNase arises from the general lack selectivity over RT polymerase (pol) and integrase (IN) strand transfer (ST) inhibitions. We report herein synthesis biochemical evaluations three novel 3-hydroxypyrimidine-2,4-dione (HPD) subtypes carefully designed to achieve selective inhibition. Biochemical studies...
Abstract HIV-1 capsid (CA) stability is important for viral replication. E45A and P38A mutations enhance reduce core stability, thus impairing infectivity. Second-site R132T T216I rescue Capsid lattice was studied by solving seven crystal structures (in native background), including P38A, P38A/T216I, E45A, E45A/R132T CA, using molecular dynamics simulations of lattices, cryo-electron microscopy assemblies, time-resolved imaging uncoating, biophysical biochemical characterization assembly...
The N348I mutation at the connection subdomain of HIV-1 reverse transcriptase (RT) confers clinically significant resistance to both nucleoside and non-nucleoside RT inhibitors (NNRTIs) by mechanisms that are not well understood. We used transient kinetics characterize enzymatic properties determine biochemical mechanism NNRTI nevirapine (NVP). demonstrate changes distant from binding pocket decrease inhibitor (increase K(d)(-NVP)) primarily decreasing association rate (k(on-NVP))....
ABSTRACT Nucleos(t)ide reverse transcriptase inhibitors (NRTIs) form the backbone of most anti-HIV therapies. We have shown that 4′-ethynyl-2-fluoro-2′-deoxyadenosine (EFdA) is a highly effective NRTI; however, reasons for potent antiviral activity EFdA are not well understood. Here, we use combination structural, computational, and biochemical approaches to examine how substitutions in sugar or adenine rings affect incorporation dA-based NRTIs like into DNA by HIV RT their susceptibility...
Human immunodeficiency virus (HIV) reverse transcriptase (RT)-associated ribonuclease H (RNase H) remains the only virally encoded enzymatic function yet to be exploited as an antiviral target. One of possible challenges may that targeting HIV RNase is confronted with a steep substrate barrier. We have previously reported 3-hydroxypyrimidine-2,4-dione (HPD) subtype potently and selectively inhibited without inhibiting in cell culture. report herein critical redesign HPD chemotype featuring...
Abstract Background The K65R substitution in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) is the major resistance mutation selected patients treated with first-line antiretroviral tenofovir disoproxil fumarate (TDF). 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA), most potent nucleoside analog RT inhibitor (NRTI) that unlike all approved NRTIs retains a 3'-hydroxyl group and has remarkable potency against wild-type (WT) drug-resistant HIVs. EFdA acts primarily as...
HIV-1 capsid protein (CA) is the molecular target of recently FDA-approved long acting injectable (LAI) drug lenacapavir (GS-6207). The quick emergence CA mutations resistant to GS-6207 necessitates design and synthesis novel sub-chemotypes. We have conducted structure-based two new sub-chemotypes combining scaffold N-terminal cap PF74 analogs, other important CA-targeting chemotype. was validated via induced-fit docking. More importantly, we worked out a general synthetic route allow...
Sublimed, low-density p-tert-butylcalix[4]arene absorbs methane more readily at room temperature and 1 atm pressure than do either single wall carbon nanotubes (SWNT) or a comparative porous metal–organic framework (MOF-1).