A5079455106- HIV Research and Treatment
- HIV/AIDS drug development and treatment
- DNA and Nucleic Acid Chemistry
- RNA and protein synthesis mechanisms
- HIV/AIDS Research and Interventions
- Monoclonal and Polyclonal Antibodies Research
- Bioactive Compounds and Antitumor Agents
- Protein Structure and Dynamics
- Click Chemistry and Applications
- Toxin Mechanisms and Immunotoxins
- Pharmacological Effects of Natural Compounds
- Morinda citrifolia extract uses
- CAR-T cell therapy research
- Microbial Metabolites in Food Biotechnology
- Enzyme Production and Characterization
- Mosquito-borne diseases and control
- Eosinophilic Disorders and Syndromes
- Cytomegalovirus and herpesvirus research
- Phytochemistry and biological activity of medicinal plants
- Synthesis and Characterization of Heterocyclic Compounds
- Galectins and Cancer Biology
- Biochemical and Molecular Research
- Digital Media and Visual Art
- Art, Politics, and Modernism
- Nanofabrication and Lithography Techniques
University of Pittsburgh
2013-2024
State Research Center of Virology and Biotechnology VECTOR
2002-2014
The rapid emergence of drug-resistant variants human immunodeficiency virus, type 1 (HIV-1), has limited the efficacy anti-acquired immune deficiency syndrome (AIDS) treatments, and new lead compounds that target novel binding sites are needed. We have determined 3.15 A resolution crystal structure HIV-1 reverse transcriptase (RT) complexed with dihydroxy benzoyl naphthyl hydrazone (DHBNH), an RT RNase H (RNH) inhibitor (RNHI). DHBNH is effective against a variety mutants. While little...
3′-Azidothymidine (AZT) was the first approved antiviral for treatment of human immunodeficiency virus (HIV). Reported efforts in clicking 3′-azido group AZT have not yielded 1,2,3-triazoles active against HIV or any other viruses. We report herein AZT-derived with submicromolar potencies HIV-1. The observed activities from cytopathic effect (CPE) based assay were confirmed through a single replication cycle assay. Structure–activity-relationship (SAR) studies revealed two structural...
Desiccation, an extreme form of dehydration, reduces the cellular water content to below 5 % and poses a major challenge for most plants. Ramonda serbica, tertiary relict homoiochlorophyllous resurrection plant, is exceptional model investigating vegetative desiccation tolerance. Late Embryogenesis Abundant (LEA) proteins are strongly involved in this adaptive trait, but their exact molecular function still unclear. In study, we report first successful recombinant production...
HIV-1 enzyme reverse transcriptase (RT) is a major target for antiviral drug development, with over half of current FDA-approved therapeutics against HIV infection targeting the DNA polymerase activity this enzyme. RT multifunctional that has RNA and dependent activity, along ribonuclease H (RNase H) activity. The latter responsible degradation viral genomic template during first strand synthesis to allow completion transcription dsDNA. While RNase been shown be essential virus infectivity,...
We report the synthesis, thermal stability, and RNase H substrate activity of 2′-deoxy-2′,4′-difluoroarabino-modified nucleic acids. 2′-Deoxy-2′,4′-difluoroarabinouridine (2,′4′-diF-araU) was prepared in a stereoselective way six steps from 2′-deoxy-2′-fluoroarabinouridine (2′-F-araU). NMR analysis quantum mechanical calculations at nucleoside level reveal that introduction 4′-fluorine introduces strong bias toward North conformation, despite presence 2′-βF, which generally steers sugar...
HIV‐1 reverse transcriptase is a bifunctional enzyme, having both DNA polymerase (RNA‐ and DNA‐dependent) ribonuclease H activities. has been an exceptionally important target for antiretroviral therapeutic development, nearly half of the current clinically used antiretrovirals polymerase. However, no inhibitors are on market or in preclinical development. Several drug‐like small molecule have described, but little structural information available about interactions between that exhibit...
4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA, MK-8591, islatravir) is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) with exceptional potency against wild-type (WT) and drug-resistant HIV-1 in phase III clinical trials. EFdA resistance not well characterized. To study patterns that may emerge naive or tenofovir (TFV)-, emtricitabine/lamivudine (FTC/3TC)-, zidovudine (AZT)-treated patients, we performed viral passaging experiments starting WT, K65R, M184V,...
Mesothelin (MSLN) has been a validated tumor-associated antigen target for several solid tumors over decade, making it an attractive option therapeutic interventions. Novel antibodies with high affinity and better properties are needed. In the current study, we have isolated characterized novel heavy chain variable (VH) domain 3C9 from large-size human immunoglobulin VH library. exhibited (KD [dissociation constant] <3 nM) binding specificity in membrane proteome array (MPA). mouse xenograft...
HIV-1 Nef is an attractive target for antiretroviral drug discovery because of its role in promoting infectivity, replication, and host immune system avoidance. Here, we applied a screening strategy which recombinant protein was coupled to activation the Src-family tyrosine kinase Hck, enhances life cycle macrophages. stimulates Hck activity
A series of DNA primers containing nucleotides with various sugar pucker conformations at the 3'-terminus were chemically synthesized by solid-phase synthesis. The ability wild-type (WT) HIV-1 reverse transcriptase (RT) and AZT-resistant (AZTr) RT to excise 3'-terminal nucleotide was assessed. Nucleosides a preference for North conformation more refractory excision both WT-RT AZTr-RT. We found that contain puckered-nucleotides can also affect translocation status RT/template/primer complex,...
The Nef protein produced by the viruses HIV-1 and SIV drives efficient viral replication partially inducing constitutive activation of host cell tyrosine kinases, including members Src Tec families. Here, we uncovered mechanism which both enhanced activity family kinase Btk in vitro cells. A mutant that could not bind to SH3 domain kinases activated same extent as did wild-type Nef, demonstrating distinct mechanisms. SH3-SH2 region formed a homodimer requiring CD loop SH2 domain, was...
The Gag-Pol polyprotein in human immunodeficiency virus type I (HIV-1) encodes enzymes that are essential for replication: protease (PR), reverse transcriptase (RT), and integrase (IN). mature forms of PR, RT IN homodimer, heterodimer tetramer, respectively. precise mechanism underlying the formation dimer or tetramer is not yet understood. Here, to gain insight into dimerization PR precursor, we prepared a model PR-RT, incorporating an inactivating mutation at active site, D25A, including...
In human immunodeficiency virus-1 (HIV-1), reverse transcriptase (RT) is encoded as a 66 kDa protein, p66, in the Gag-Pol polyprotein. This protein proteolytically cleaved by HIV-1 protease (PR) to finally generate mature RT that heterodimer, composed of p66 subunit and p66-derived 51 subunit, p51. our prior work, we demonstrated tRNALys3 binding p66/p66 facilitates efficient cleavage p51 PR. However, known be recruited virus forming complex with lysyl–tRNA synthetase (LysRS). Herein, tested...
HIV-1 reverse transcriptase (RT) is a heterodimer comprised p66 and p51 subunits (p66/p51). Several single amino acid substitutions in RT, including L289K, decrease p66/p51 dimer affinity, reduce enzymatic functioning. Here, small-angle X-ray scattering (SAXS) with proton paramagnetic relaxation enhancement (PRE),
A clinically-relevant, drug-resistant mutant of HIV-1 protease (PR), termed Flap+(I54V) and containing L10I, G48V, I54V V82A mutations, is known to produce significant changes in the entropy enthalpy balance drug-PR interactions, compared wild-type PR. similar mutant, Flap+(I54A) , which evolves from contains single change at residue 54 relative does not. Yet, how behaves solution not known. To understand molecular basis V54A evolution, we nuclear magnetic resonance (NMR) spectroscopy,...
Abstract Antibody based therapeutics targeting mesothelin (MSLN) have shown limited anticancer activity in clinical trials. Novel antibodies with high affinity and better therapeutic properties are needed. In the current study, we isolated characterized a novel VH domain 3C9 from large size human immunoglobulin heavy chain variable (VH) library. exhibited [KD (dissociation constant) < 3 nM] binding specificity membrane proteome array (MPA). mouse xenograft model, fused to Fc became...
Abstract Among the immunoglobulin domains, CH2 domain has lowest thermal stability, which also depends on amino acid sequence and buffer conditions. To further identify factors that influence folding we characterized in reduced form using differential scanning fluorimetry nuclear magnetic resonance. We show can fold, similarly to disulfide‐bridged form, without forming a disulfide‐bridge, even though protein contains two Cys residues. Although exhibits stability more than 15°C lower it does...