Design and Synthesis of HIV Integrase as Potential Anti-AIDS Drugs

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FDA-approved inhibitors of HIV-1 IN belong to a class of drugs called " integrase strand transfer inhibitors" (INSTIs), due to their ability to preferentially block the enzyme's strand transfer (ST) reaction as compared to the enzymes 3'-processing (3'-P) reaction. Unfortunately, mutant forms of IN arise that lead to clinical resistance against these INSTIs. This adds impetus to a continuing need to develop next-generation agents that have the ability to retain high antiviral efficacy against emerging strains of INSTI-resistant virus. Utilizing my laboratory's design and synthetic capabilities, we have teamed with pharmacologists (Dr. Yves Pommier, NCI), virologists (Dr. Hughes, NCI) and structural biologists (Dr. Robert Craigie, NIDDK, Dr. Dmitry Lyumkis, the Salk Institute and Dr. Cherepanov, the Francis Crick Institute, UK) to better understand the interactions of INSTIs with intasomes (multimeric integrase with DNA substrate and metal cofactor) and the roles that mutations play in down-regulating these interactions. Cryo-EM has played a key role in these efforts. Cryo-EM structures of our best INSTIs bound to intasomes revealed a complex and dynamic network of water molecules surrounding bound INSTIs, with many of these waters appearing to be conserved and occupying similar positions in the unliganded and INSTI-bound structures. However, some waters are displaced or shifted as a consequence of binding of the INSTI; others are found only when INSTIs are bound, suggesting that the conformational changes induced by the binding stabilize their position. We concluded that within the "substrate envelope" (the region defined by the binding of host and viral DNA), differences in geometry of the catalytic pockets, their overall volume, the nearby patterns of hydration, among other features, all matter for understanding INSTI interactions. We also have a collaboration in place with the Imperial College London laboratory of Dr. Goedele Maertens to examine a diverse selection of our IN inhibitors against human T-cell leukemia virus type 1 (HTLV-1) and a number of our synthetic constructs show significant potency against this target. Our best INSTs exhibit better antiviral profiles than current FDA-approved agents when assayed in single round replication assays that employ a panel of more than 100 drug-resistant mutant forms of integrase. In order to generate key pharmacokinetic (PK) data on our best INSITs, we have partnered with the NCI Invention Development Program (IDP) to obtain early-stage PK data, including studies in rodents.