Biological and structural analysis of new potent Integrase-LEDGF allosteric HIV-1 inhibitors

Abstract

LEDGF/p75 (LEDGF) main cellular cofactor of HIV-1 integrase (IN), acts as tethering factor to target integration of HIV in actively transcribed genes. Recently a class of IN inhibitors based on inhibition of LEDGF-IN interaction has been developed. We describe here a new series of IN-LEDGF allosteric inhibitors (INLAIs), with potent anti-HIV-1 activity in the one-digit nanomolar range. These compounds inhibited IN-LEDGF interaction while enhancing IN-IN aberrant multimerization by allosteric mechanism. Compounds of this series were fully active on HIV-1 mutants resistant to IN strand transfer inhibitors (INSTIs) and other class of anti-HIV drugs, confirming that they belong to a new class of antiretrovirals. These compounds displayed most potent antiretroviral activity at post-integration due to aberrant IN polymerization responsible of infectivity defect of viral particles produced. INLAI-resistant mutants were selected by dose escalation method and the most detrimental mutation found was T174I. The impact of these resistance mutations was analyzed by fold shift EC50 with regard to wild type virus and the replication capacity of mutated viruses were determined. Crystal structure of BDM-2, the lead compound of this series in complex with IN catalytic core domain (CCD) was elucidated. No antagonism was observed between BDM-2 and a panel of 16 antiretroviral drugs from different classes. In conclusion, the overall virologic profile of BDM-2 warrants the recently completed single ascending dose phase I trial (ClinicalTrials.gov Id:NCT03634085) and supports further clinical investigation for potential use in combination with other antiretroviral drugs.