A5028671509- HIV/AIDS drug development and treatment
- HIV Research and Treatment
- Biochemical and Molecular Research
- Cyclopropane Reaction Mechanisms
- Cytomegalovirus and herpesvirus research
- RNA modifications and cancer
- vaccines and immunoinformatics approaches
- HIV/AIDS Research and Interventions
- Hepatitis C virus research
- Cancer-related gene regulation
- Bacteriophages and microbial interactions
- Advanced biosensing and bioanalysis techniques
- Viral-associated cancers and disorders
- Biochemical and Structural Characterization
- RNA Research and Splicing
- Blood groups and transfusion
- Antimicrobial Peptides and Activities
University of Colorado Denver
2017-2024
University of Colorado Anschutz Medical Campus
2019-2022
The Ohio State University
2016-2018
Allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are a promising new class of antiretroviral agents that disrupt proper viral maturation by inducing hyper-multimerization IN. Here we show lead pyridine-based ALLINI KF116 exhibits striking selectivity for IN tetramers versus lower order protein oligomers. structural features essential its functional tetramerization and replication also critically important mediated higher-order multimerization. Live cell imaging single particles revealed...
A large number of human immunodeficiency virus 1 (HIV-1) integrase (IN) alterations, referred to as class II substitutions, exhibit pleiotropic effects during replication. However, the underlying mechanism for phenotype is not known. Here we demonstrate that all tested IN substitutions compromised IN-RNA binding in virions by one three distinct mechanisms: (i) markedly reducing levels thus precluding formation complexes with viral RNA; (ii) adversely affecting functional multimerization and...
Allosteric integrase inhibitors (ALLINIs) are a class of experimental anti-HIV agents that target the noncatalytic sites viral (IN) and interfere with IN-viral RNA interaction during maturation. Here, we report highly potent safe pyrrolopyridine-based ALLINI, STP0404, displaying picomolar IC 50 in human PBMCs >24,000 therapeutic index against HIV-1. X-ray structural biochemical analyses revealed STP0404 binds to host LEDGF/p75 protein binding pocket IN dimer, which induces aberrant...
ABSTRACT Recent evidence indicates that inhibition of HIV-1 integrase (IN) binding to the viral RNA genome by allosteric inhibitors (ALLINIs) or through mutations within IN yields aberrant particles in which ribonucleoprotein complexes (vRNPs) are eccentrically localized outside capsid lattice. These noninfectious and blocked at an early reverse transcription stage target cells. However, basis this defect is unknown. Here, we show from ALLINI-treated virions prematurely degraded cells,...
Allosteric HIV-1 integrase inhibitors (ALLINIs) are a new class of potential antiretroviral therapies with unique mechanism action and drug resistance profile. To further extend this via scaffold hopping approach, we have synthesized series analogues possessing an isoquinoline ring system. Lead compound 6l binds in the v-shaped pocket at IN dimer interface is highly selective for promoting higher-order multimerization inactive over inhibiting IN-LEDGF/p75 binding. Importantly, potently...
Abstract Human defensins are innate immune defense peptides with a remarkably broad repertoire of anti-pathogen activities. In addition to modulating response, inflammation and angiogenesis, disintegrating bacterial membranes inactivating toxins, known intercept various viruses at different stages their life cycles, while remaining relatively benign towards human cells proteins. Recently we have found that inactivate proteinaceous toxins by taking advantage low thermodynamic stability acting...
Human immunodeficiency virus-1 (HIV-1) is the causative agent of acquired syndrome (AIDS). HIV-1, like all retroviruses, stably integrates its vDNA copy into host chromatin, a process allowing for permanent infection. This essential step HIV-1 replication catalyzed by viral integrase (IN) and aided cellular protein LEDGF/p75. In addition, IN also crucial proper virion maturation as it interacts with RNA genome to ensure encapsulation ribonucleoprotein complexes within protective capsid core....
Abstract Background During HIV-1 maturation, Gag and Gag-Pol polyproteins are proteolytically cleaved the capsid protein polymerizes to form honeycomb lattice. integrase (IN) binds viral genomic RNA (gRNA) impairment of IN-gRNA binding leads mis-localization nucleocapsid (NC)-condensed ribonucleoprotein complex outside core. IN NC were previously demonstrated bind gRNA in an orthogonal manner virio; however, effect alone or simultaneous both proteins on structure is not yet well understood....
The HIV-1 integrase (IN) plays a critical role in the viral lifecycle by integrating DNA into host chromosome. catalytic function of IN has been exploited as target, with five drugs acting active site binders (IN strand transfer inhibitors, INSTIs). However, mutations conferring low-level resistance to INSTIs have reported. Therefore, new inhibitors different mechanisms action are needed. allosteric inhibition IN, exerted (ALLINIs), is gaining interest. ALLINIs inhibit inducing aberrant...
ABSTRACT A large number of HIV-1 integrase (IN) alterations, referred to as class II substitutions, exhibit pleotropic effects during virus replication. However, the underlying mechanism for phenotype is not known. Here we demonstrate that all tested IN substitutions compromised IN-RNA binding in virions by one three distinct mechanisms: i) markedly reducing levels thus precluding formation complexes with viral RNA; ii) adversely affecting functional multimerization and consequently...
Abstract Background The internal N 6 -methyladenosine (m A) modification of cellular mRNA regulates post-transcriptional gene expression. YTH domain family proteins (YTHDF1-3, or Y1-3) bind to m A-modified and modulate its metabolism processing, thereby affecting protein translation in cells. We previously reported that HIV-1 RNA contains A Y1-3 inhibit infection by decreasing reverse transcription. Here we extended our studies further understand the mechanisms Y1-3-mediated inhibition viral...
Abstract Recent findings indicate a key role for the HIV-1 integrase (IN) enzyme in proper virion morphogenesis which involves its binding to viral RNA. Mutations within IN C-terminal domain potently block IN-RNA interactions leading generation of non-infectious particles with “eccentric” morphology genomic RNA mislocalized outside capsid core. Despite containing all components necessary replication, such cannot successfully infect target cells. Interestingly, mutations at residues...