HIV-1 integrase tetramers are the antiviral target of pyridine-based allosteric integrase inhibitors

Title : HIV-1 integrase tetramers are the antiviral target of pyridine-based allosteric integrase inhibitors

Abstract:

Allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are a promising new class of antiretroviral agents that disrupt proper viral maturation by inducing hyper-multimerization of IN. Here we show that lead pyridine-based ALLINI KF116 exhibits striking selectivity for IN tetramers versus lower order protein oligomers. Paradoxically, IN structural features, which are essential for its functional tetramerization and HIV-1 replication, are also critically important for KF116 mediated higher-order IN multimerization. Live cell imaging of single viral particles revealed that KF116 treatment during virion production compromises the tight association of IN with capsid cores during subsequent infection of target cells. We have synthesized the highly active (-)-KF116 enantiomer, which displayed EC₅₀ of ~7 nM against wild type HIV-1 and ~10-fold higher, sub-nM activity against a clinically relevant dolutegravir resistant mutant virus suggesting potential clinical benefits for complementing dolutegravir therapy with pyridine-based ALLINIs.

Biography:

Dr. Mamuka Kvaratskhelia began his independent research career at the Ohio State University in 2003 and his research has been focused on better understanding of the structure and function of HIV-1 integrase as a therapeutic target. He has recently (2017) moved to University of Colorado Denver as a Professor of Medicine (Infectious Diseases) to further extend his studies on HIV-1 integrase. By employing innovative biochemical, biophysical, structural biology, molecular biology and virology approaches, his research team has made many important contributions to the field, which include the discovery of second, non-catalytic role of integrase in HIV-1 biology and elucidating the mode of action of allosteric HIV-1 integrase inhibitors (ALLINIs), which are currently in pre-clinical trials.