A New Class of Multimerization Selective Inhibitors of HIV-1 Integrase

PLoS Pathogens

Amit Sharma¹  Mamuka Kvaratskhelia¹  Alison Slaughter¹  Lei Feng¹  Jacques J. Kessl¹  Li Wu²  Hind J. Fadel³  Eric Poeschla³  James R. Fuchs⁴  Nivedita Jena⁴  Frances Male⁵  Nirav Malani⁵  Frederic D. Bushman⁵ 

[1] Center for Retrovirus Research and College of Pharmacy, The Ohio State University, Columbus, Ohio, United States of America;Center for Retrovirus Research and Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio, United States of America;Department of Molecular Medicine & Division of Infectious Diseases, Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America;Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio, United States of America;Perelman School of Medicine, Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America

关键词: HIV-1;    Virions;    Reverse transcription;    Polymerase chain reaction;    Viral replication;    Crystal structure;    Diluents;    Quinolines;   

DOI  :  10.1371/journal.ppat.1004171

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY