A5033031134- HIV/AIDS drug development and treatment
- HIV Research and Treatment
- Biochemical and Molecular Research
- Advanced machining processes and optimization
- Click Chemistry and Applications
- Synthetic Organic Chemistry Methods
- Cancer therapeutics and mechanisms
- Asymmetric Synthesis and Catalysis
- Advanced Surface Polishing Techniques
- Microbial Natural Products and Biosynthesis
- Synthesis and Catalytic Reactions
- Protein Degradation and Inhibitors
- Phenothiazines and Benzothiazines Synthesis and Activities
- Chemical Synthesis and Analysis
- Metal Alloys Wear and Properties
- Glycosylation and Glycoproteins Research
- HIV/AIDS Research and Interventions
- Alkaloids: synthesis and pharmacology
- Essential Oils and Antimicrobial Activity
- Computational Drug Discovery Methods
- Chemical synthesis and alkaloids
- Synthesis and Biological Evaluation
- Cyclopropane Reaction Mechanisms
- Cancer-related Molecular Pathways
- Industrial Technology and Control Systems
Frederick National Laboratory for Cancer Research
2016-2025
National Institutes of Health
2015-2025
National Cancer Institute
2016-2025
Center for Cancer Research
2016-2025
Jilin Agricultural Science and Technology University
2016-2024
Northwest University
2019-2024
Jilin Agricultural University
2015-2024
Beijing Academy of Agricultural and Forestry Sciences
2023
Ministry of Agriculture and Rural Affairs
2023
Northeast Agricultural University
2022
Integrase strand transfer inhibitors (INSTIs) are the class of antiretroviral (ARV) drugs most recently approved by FDA for treatment HIV-1 infections. INSTIs block reaction catalyzed integrase (IN) and have been shown to potently inhibit infection wild-type HIV-1. Of three current FDA-approved INSTIs, Dolutegravir (DTG), has effective, in part because does not readily select resistant mutants. However, recent studies showed that when INSTI-experienced patients put on a DTG-salvage therapy,...
Strengths and weaknesses of an HIV drug Retroviruses replicate by inserting a copy their RNA, which has been reverse transcribed into DNA, the host genome. This process involves intasome, nucleoprotein complex comprising copies viral integrase bound at ends DNA. strand-transfer inhibitors (INSTIs) stop from replicating blocking are widely used in treatment. Cook et al. describe structures second-generation to simian immunodeficiency virus (SIV) intasome with mutations known cause resistance....
Abstract Proteasome–ubiquitin receptor hRpn13/Adrm1 binds and activates deubiquitinating enzyme Uch37/UCHL5 is targeted by bis-benzylidine piperidone RA190, which restricts cancer growth in mice xenografts. Here, we solve the structure of hRpn13 with a segment hRpn2 that serves as its proteasome docking site; proline-rich C-terminal extension stretches across narrow canyon ubiquitin-binding Pru domain blocking an RA190-binding surface. Biophysical analyses combination cell-based assays...
HIV-1 infection depends on the integration of viral DNA into host chromatin. Integration is mediated by enzyme integrase and blocked strand transfer inhibitors (INSTIs), first-line antiretroviral therapeutics widely used in clinic. Resistance to even best INSTIs a problem, mechanisms resistance are poorly understood. Here, we analyze combinations mutations E138K, G140A/S, Q148H/K/R, which confer INSTIs. The investigational drug 4d more effectively inhibited mutants compared with approved...
Integrase mutations can reduce the effectiveness of first-generation FDA-approved integrase strand transfer inhibitors (INSTIs), raltegravir (RAL) and elvitegravir (EVG). The second-generation agent, dolutegravir (DTG), has enjoyed considerable clinical success; however, resistance-causing that diminish efficacy DTG have appeared. Our current findings support extend substrate envelope concept broadly effective INSTIs be designed by filling defined DNA substrates. Previously, we explored...
Aspergillus flavus produces highly toxic and carcinogenic aflatoxins that cause severe economic losses pose a serious threat to public health. Cinnamon essential oils (CEO) have recently attracted attention as promising alternative antifungal agents. In this study, the inhibition mechanism of CEO on A. was investigated, its application in prevention coix seeds explored for first time. The results showed mycelial growth, spore germination, aflatoxin synthesis were completely inhibited after...
Second-generation integrase strand transfer inhibitors (INSTIs) are strongly recommended for people living with HIV-1 (PLWH). The emergence of resistance to second-generation INSTIs has been infrequent and not yet a major issue in high-income countries. However, the delayed rollouts these low- middle-income countries during COVID-19 pandemic combined increased transmission drug-resistant mutants worldwide leading an increase INSTI resistance. Herein, we evaluated antiviral potencies our lead...
Application of copper-catalyzed azide–alkyne cycloaddition (CuAAC) “click” reactions assemble bivalent proteolysis-targeting chimeras (PROTACs) constituents targeting tyrosyl-DNA phosphodiesterase 1 (TDP1).
Aryl amines serve as fundamental building blocks in the production of many pharmaceuticals, agrochemicals, and functional materials, underscoring their preparation synthetic chemistry. This work presents an approach that combines...
HIV integrase (IN) strand transfer inhibitors (INSTIs) are among the newest anti-AIDS drugs; however, mutant forms of IN can confer resistance. We developed noncytotoxic naphthyridine-containing INSTIs that retain low nanomolar IC50 values against HIV-1 variants harboring all major INSTI-resistant mutations. found by analyzing crystal structures bound to from prototype foamy virus (PFV) most successful show striking mimicry viral DNA prior 3'-processing and host transfer. Using this concept...
We tested three compounds for their ability to inhibit the RNase H (RH) and polymerase activities of HIV-1 reverse transcriptase (RT). A high-resolution crystal structure (2.2 Å) one showed that it chelates two magnesium ions at RH active site; this prevents site from interacting with, cleaving, RNA strand an RNA-DNA heteroduplex. The were using a variety substrates: all inhibited polymerase-independent activity RT. Time-of-addition experiments more potent if they bound RT before nucleic...
Using small molecule microarray TDP1 inhibitors have been identified that bind in a trivalent mode.
On the basis of a series lactam and phthalimide derivatives that inhibit HIV-1 integrase, we developed new molecule, XZ-259, with biochemical antiviral activities comparable to raltegravir. We determined crystal structures XZ-259 four other in complex prototype foamy virus intasome. The compounds bind at integrase-Mg2+-DNA interface integrase active site. In assays, inhibits raltegravir-resistant integrases harboring Y143R mutation. Molecular modeling is also presented suggesting can...
There are currently three HIV-1 integrase (IN) strand transfer inhibitors (INSTIs) approved by the FDA for treatment of AIDS. However, emergence drug-resistant mutants emphasizes need to develop additional agents that have improved efficacies against existent resistant mutants. As reported herein, we modified our recently disclosed 1-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamides IN compounds recombinant in biochemical assays. These new show single-digit nanomolar antiviral...
Integrase (IN) inhibitors are the newest class of antiretroviral agents developed for treatment HIV-1 infections. Merck's Raltegravir (RAL) (October 2007) and Gilead's Elvitegravir (EVG) (August 2012), which act as IN strand transfer (INSTIs), were first anti-IN drugs to be approved by FDA. However, virus develops resistance both RAL EVG, there is extensive cross-resistance these two drugs. New "2nd-generation" INSTIs needed that will have greater efficacy against RAL- EVG-resistant strains...