A5008610083- HIV Research and Treatment
- HIV/AIDS drug development and treatment
- HIV/AIDS Research and Interventions
- Biochemical and Molecular Research
- Cytomegalovirus and herpesvirus research
- Neuroscience and Neuropharmacology Research
- Receptor Mechanisms and Signaling
- Immune Cell Function and Interaction
- Click Chemistry and Applications
- Peptidase Inhibition and Analysis
- Hepatitis B Virus Studies
- Inflammation biomarkers and pathways
- Immune Response and Inflammation
- Bioactive Compounds and Antitumor Agents
- Pharmacological Receptor Mechanisms and Effects
- Mosquito-borne diseases and control
- Spectroscopy Techniques in Biomedical and Chemical Research
- Hepatitis C virus research
- Monoclonal and Polyclonal Antibodies Research
- RNA Research and Splicing
- S100 Proteins and Annexins
- CRISPR and Genetic Engineering
- Advanced biosensing and bioanalysis techniques
- HIV-related health complications and treatments
- Pneumocystis jirovecii pneumonia detection and treatment
Merck & Co., Inc., Rahway, NJ, USA (United States)
2022-2025
United States Military Academy
2009-2023
University of Pennsylvania
2005-2010
University of Rochester Medical Center
2009
University of Rochester
2003-2004
Texas Biomedical Research Institute
2001
Islatravir (ISL) is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) that inhibits human immunodeficiency virus (HIV) transcription by blocking (RT) on the primer:template. ISL being developed for treatment of HIV-1 infection.
Antiretroviral therapy inhibits HIV-1 replication but is not curative due to establishment of a persistent reservoir after virus integration into the host genome. Reservoir reduction therefore an important cure strategy. Some nonnucleoside reverse transcriptase inhibitors induce selective cytotoxicity in vitro require concentrations far exceeding approved dosages. Focusing on this secondary activity, we found bifunctional compounds with HIV-1–infected cell kill potency at clinically...
ABSTRACT Islatravir (ISL) is a deoxyadenosine analog that inhibits HIV-1 reverse transcription by multiple mechanisms. Lenacapavir (LEN) novel capsid inhibitor at stages throughout the viral life cycle. ISL and LEN are being investigated as once-weekly combination oral therapy for treatment of HIV-1. Here, we characterized in vitro to assess combinatorial antiviral activity, cytotoxicity, potential interactions between two compounds. Bliss analysis revealed with demonstrated additive...
Despite the success of combination antiretroviral therapy (cART) to suppress HIV replication, persists in a long-lived reservoir that can give rise rebounding viremia upon cART cessation. The translationally active consists HIV-infected cells continue produce viral proteins even presence cART. These are implicated resultant cessation and likely contribute chronic immune activation people living with (PLWH) on Methodologies quantify needed. Here, an automated immunocytochemistry (ICC) assay...
Using the HIV-1 protease binding mode of MK-8718 and PL-100 as inspiration, a novel aspartate bicyclic piperazine sulfonamide core was designed synthesized. The resulting inhibitor containing this showed an 60-fold increase in enzyme affinity 10-fold antiviral activity relative to MK-8718.
The mechanisms controlling retroviral integration have been the topic of intense interest, in part because adverse clinical events that occurred during retrovirus-mediated human gene therapy. Here we investigate use artificial tethering interactions to constrain site selection an vitro model. During normal infection, HIV DNA is favored active cellular transcription units. One component targeting mechanism LEDGF/p75 protein. binds tightly integrase (IN) protein, and depletion from target...
Although current antiretroviral therapy can control HIV-1 replication and prevent disease progression, it is not curative. Identifying mechanisms that lead to eradication of persistent viral reservoirs in people living with (PLWH) remains an outstanding challenge achieving cure. Utilizing a phenotypic screen, we identified novel chemical class capable killing infected peripheral blood mononuclear cells. Tool compounds ICeD-1 ICeD-2 ("inducer cell death-1 2"), optimized for potency...
Doravirine (DOR), a non-nucleoside reverse transcriptase inhibitor (NNRTI), was approved for treatment of HIV-1 infection in 2018. In the pivotal phase 3 trials, DRIVE-FORWARD and DRIVE-AHEAD, 7 out 747 (0.9%) treatment-naive participants treated with DOR plus two nucleos(t)ide inhibitors (NRTIs) met protocol-defined virologic failure criteria showed phenotypic resistance to at week 48. The most common resistance-associated mutation (RAM) detected 5 resistant isolates F227C. Six bearing NRTI...
A novel HIV protease inhibitor was designed using a morpholine core as the aspartate binding group. Analysis of crystal structure initial lead bound to enabled optimization enzyme potency and antiviral activity. This afforded series potent orally bioavailable inhibitors which MK-8718 identified compound with favorable overall profile.
Integrase (IN) is the catalytic component of preintegration complex, a large nucleoprotein assembly critical for integration retroviral genome into host chromosome. Although partial crystal structures human immunodeficiency virus IN alone and its complex with integrase binding domain factor PSIP1/lens epithelium-derived growth (LEDGF)/p75 are available, many questions remain regarding properties LEDGF-bound oligomers. Using analytical ultracentrifugation, multiangle light scattering, small...
Paired metal ions have been proposed to be central the catalytic mechanisms of RNase H nucleases, bacterial transposases, Holliday junction resolvases, retroviral integrases and many other enzymes. Here we present a sensitive assay for DNA transesterification in which catalysis by human immunodeficiency virus-type 1 (HIV-1) integrase (IN) connects two strands (disintegration reaction), allowing detection using quantitative PCR (qPCR). We evidence suggesting that three acidic residues IN...
We have recently reported that the reverse transcriptase (RT) of SIVMNE 170 (170), which is a representative viral clone late symptomatic phase infection with parental strain, CL8 (CL8), has largely increased fidelity, compared RT. In present study, we analyzed mechanistic alterations high fidelity RT variant. First, found among several mutations, only one, V148I, solely responsible for increase over This V148I mutation lies near Gln-151 residue important to low and binding incoming dNTPs....
Allosteric integrase inhibitors (ALLINIs) bind to the lens epithelial-derived growth factor (LEDGF) pocket on HIV-1 (IN) and possess potent antiviral effects. Rather than blocking proviral integration, ALLINIs trigger IN conformational changes that have catastrophic effects viral maturation, rendering virions assembled in presence of noninfectious. A high-throughput screen for compounds disrupt IN·LEDGF interaction was executed, extensive triage led identification a t-butylsulfonamide...
ABSTRACT Following the completion of reverse transcription, human immunodeficiency virus integrase (IN) enzyme covalently links viral cDNA to a host cell chromosome. An IN multimer carries out this reaction, but roles individual monomers within complex are mostly unknown. Here we analyzed distribution functions for target DNA capture and catalysis multimer. We used forced complementation between pairs deletion derivatives in vitro as tool probing cis-trans relationships amino acid...
Modification of potent, selective metabotropic glutamate receptor 2 negative allosteric modulator (mGluR2 NAM) led to a series analogues with excellent binding affinity, lipophilicity, and suitable physicochemical properties for PET tracer convenient chemical handles incorporation 11C or 18F radiolabel. [11C]MK-8056 was synthesized evaluated in vivo demonstrated appropriate selectivity, be used as positron emission tomography mGluR2.
Here we report enzymatic variations among the reverse transcriptases (RTs) of five simian immunodeficiency virus (SIV) strains, Sab-1, 155-4, Gri-1, 9063-2, and Tan-1, which were isolated from four different species naturally infected African green monkeys living in regions across Africa. First, Sab-1 RT exhibits most efficient dNTP incorporation efficiency at low concentrations, whereas other SIVagm proteins display levels reduced polymerase activity concentrations. Tan-1 exhibited...
Abstract Background In a phase 3 trial, letermovir was noninferior to valganciclovir for cytomegalovirus (CMV) disease prophylaxis in kidney transplant recipients who were CMV-seronegative and received kidneys from donors CMV-seropositive. Genotypic antiviral resistance CMV glycoprotein B (gB) genotype are reported. Methods Plasma samples with detectable DNA sequenced the presence of known resistance-associated amino acid substitutions (RASs) encoded by gene regions (UL51, UL54, UL56, UL89,...