Abstract
HIV integrase (IN) strand transfer inhibitors (INSTIs) are among the newest anti-AIDS drugs; however, mutant forms of IN can confer resistance. We developed noncytotoxic naphthyridine-containing INSTIs that retain low nanomolar IC50 values against HIV-1 variants harboring all of the major INSTI-resistant mutations. We found by analyzing crystal structures of inhibitors bound to the IN from the prototype foamy virus (PFV) that the most successful inhibitors show striking mimicry of the bound viral DNA prior to 3′-processing and the bound host DNA prior to strand transfer. Using this concept of “bi-substrate mimicry,” we developed a new broadly effective inhibitor that not only mimics aspects of both the bound target and viral DNA but also more completely fills the space they would normally occupy. Maximizing shape complementarity and recapitulating structural components encompassing both of the IN DNA substrates could serve as a guiding principle for the development of new INSTIs.
Highlights
The emergence of resistance is a limitation for all anti-HIV therapeutics, including integrase strand transfer inhibitors (INSTIs), and resistant forms of the virus have been isolated from patients who received raltegravir (RAL, 1) or elvitegravir (EVG, 2), the first two INSTIs approved by the FDA for the treatment of HIV/AIDS.[4,6,7]
Articles resistant forms of IN have largely been empirical. This is in spite of the availability of “cocrystal” structures of the leading first and second-generation INSTIs bound to the intasome formed by the othologous enzyme from prototype foamy virus (PFV) in a complex with metal cofactors and the cognate viral DNA substrate.[18−21] these advances elucidated the structural basis for INSTI function, they have not yet led to principles that can guide the design of the generation INSTIs, which would retain effectiveness against the known resistant IN mutants.[16,22]
Our findings suggest that employing aspects of molecular mimicry of viral and host DNA may be useful in the design of improved INSTIs
Summary
Articles resistant forms of IN have largely been empirical. This is in spite of the availability of “cocrystal” structures of the leading first and second-generation INSTIs bound to the intasome formed by the othologous enzyme from prototype foamy virus (PFV) in a complex with metal cofactors and the cognate viral DNA substrate (referred to as the “intasome”).[18−21] these advances elucidated the structural basis for INSTI function, they have not yet led to principles that can guide the design of the generation INSTIs, which would retain effectiveness against the known resistant IN mutants.[16,22]. We empirically varied the structure of our recently disclosed 1-hydroxy-2-oxo-1,8-naphthyridine-containing INSTIs (4) to improve their ability to potently block in cell culture, the replication of a panel of HIV-1 based vectors that carry all of the major INSTI-resistant IN mutants.[23,24] We obtained “cocrystal” structures of the PFV intasome with the best inhibitors and found that when they bind to IN, they show striking mimicry of the binding of viral DNA in its initial state, prior to the cleavage of the dinucleotide in the 3′-P reaction. INSTIs typically include a halobenzyl ring that stacks against the base of the penultimate deoxycytidine near the processed 3′-end of the viral DNA (shown in blue in Figure 1).[3,26] Our long-term goal is to develop small molecules that are active against IN mutants that are resistant to current INSTIs. Initially, our efforts were directed at the retention of efficacy against the Y143R and N155H mutants and the double mutant, Q148H/G140S.13−16. These values are similar to those displayed by DTG; DTG is more potent than 4a against the Q148H/G140S double mutant (4a EC50 ≃ 35 nM; DTG EC50 ≃ 6 nM).[24]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
