Journal article
A new class of multimerization selective inhibitors of HIV-1 integrase
PLoS pathogens, Vol.10(5), pp.e1004171-e1004171
05/2014
DOI: 10.1371/journal.ppat.1004171
PMCID: PMC4038613
PMID: 24874515
Abstract
The quinoline-based allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are promising candidates for clinically useful antiviral agents. Studies using these compounds have highlighted the role of IN in both early and late stages of virus replication. However, dissecting the exact mechanism of action of the quinoline-based ALLINIs has been complicated by the multifunctional nature of these inhibitors because they both inhibit IN binding with its cofactor LEDGF/p75 and promote aberrant IN multimerization with similar potencies in vitro. Here we report design of small molecules that allowed us to probe the role of HIV-1 IN multimerization independently from IN-LEDGF/p75 interactions in infected cells. We altered the rigid quinoline moiety in ALLINIs and designed pyridine-based molecules with a rotatable single bond to allow these compounds to bridge between interacting IN subunits optimally and promote oligomerization. The most potent pyridine-based inhibitor, KF116, potently (EC50 of 0.024 µM) blocked HIV-1 replication by inducing aberrant IN multimerization in virus particles, whereas it was not effective when added to target cells. Furthermore, KF116 inhibited the HIV-1 IN variant with the A128T substitution, which confers resistance to the majority of quinoline-based ALLINIs. A genome-wide HIV-1 integration site analysis demonstrated that addition of KF116 to target or producer cells did not affect LEDGF/p75-dependent HIV-1 integration in host chromosomes, indicating that this compound is not detectably inhibiting IN-LEDGF/p75 binding. These findings delineate the significance of correctly ordered IN structure for HIV-1 particle morphogenesis and demonstrate feasibility of exploiting IN multimerization as a therapeutic target. Furthermore, pyridine-based compounds present a novel class of multimerization selective IN inhibitors as investigational probes for HIV-1 molecular biology.
Details
- Title: Subtitle
- A new class of multimerization selective inhibitors of HIV-1 integrase
- Creators
- Amit Sharma - Center for Retrovirus Research and College of Pharmacy, The Ohio State University, Columbus, Ohio, United States of AmericaAlison Slaughter - Center for Retrovirus Research and College of Pharmacy, The Ohio State University, Columbus, Ohio, United States of AmericaNivedita Jena - Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio, United States of AmericaLei Feng - Center for Retrovirus Research and College of Pharmacy, The Ohio State University, Columbus, Ohio, United States of AmericaJacques J Kessl - Center for Retrovirus Research and College of Pharmacy, The Ohio State University, Columbus, Ohio, United States of AmericaHind J Fadel - Department of Molecular Medicine & Division of Infectious Diseases, Mayo Clinic College of Medicine, Rochester, Minnesota, United States of AmericaNirav Malani - Perelman School of Medicine, Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of AmericaFrances Male - Perelman School of Medicine, Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of AmericaLi Wu - Center for Retrovirus Research and Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio, United States of AmericaEric Poeschla - Department of Molecular Medicine & Division of Infectious Diseases, Mayo Clinic College of Medicine, Rochester, Minnesota, United States of AmericaFrederic D Bushman - Perelman School of Medicine, Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of AmericaJames R Fuchs - Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio, United States of AmericaMamuka Kvaratskhelia - Center for Retrovirus Research and College of Pharmacy, The Ohio State University, Columbus, Ohio, United States of America
- Resource Type
- Journal article
- Publication Details
- PLoS pathogens, Vol.10(5), pp.e1004171-e1004171
- DOI
- 10.1371/journal.ppat.1004171
- PMID
- 24874515
- PMCID
- PMC4038613
- NLM abbreviation
- PLoS Pathog
- ISSN
- 1553-7366
- eISSN
- 1553-7374
- Publisher
- Public Library of Science; United States
- Grant note
- R01 AI104483 / NIAID NIH HHS\nR01 AI077344 / NIAID NIH HHS\nR21 AI110270 / NIAID NIH HHS\nR01 AI110310 / NIAID NIH HHS
- Language
- English
- Date published
- 05/2014
- Academic Unit
- Microbiology and Immunology
- Record Identifier
- 9984001107502771
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