HIV-1 integrase inhibitors that are broadly effective against drug-resistant mutants [PublishAheadOfPrint]

Integrase strand transfer inhibitors (INSTIs) have emerged as clinically effective therapeutics that inhibit HIV-1 replication by blocking the strand transfer reaction, catalyzed by HIV-1 integrase (IN). Of the three FDA-approved INSTIs, Dolutegravir (DTG) is the least apt to select for resistance. However, recent salvage therapy regimens had low response rates with therapies that included DTG, suggesting that DTG resistance can be selected in patients.

Using a single-round infection assay, we evaluated a collection of our best inhibitors and DTG against a broad panel of INSTI-resistant mutants. Two of the new compounds, 4c and 4d, had superior antiviral profiles against the mutants we tested compared to DTG.

The susceptibility profiles of 4c and 4d suggest that these compounds are candidates for development as INSTIs. Modeling the binding of 4d to HIV-1 IN reinforced the significance of mimicking the DNA substrate in developing compounds that broadly effective in their ability to inhibit HIV-1 INs with mutations in the active site.

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