RESUMO
Integrase strand transfer inhibitors (INSTIs) are the most prescribed anchor drug in antiretroviral therapy. Today, there is an increasing need for long-acting treatment of HIV-1 infection. Improving drug pharmacokinetics and anti-HIV-1 activity are key to developing more robust inhibitors suitable for long-acting formulations, but 2nd-generation INSTIs have chiral centers, making it difficult to conduct further exploration. In this study, we designed aza-tricyclic and aza-bicyclic carbamoyl pyridone scaffolds which are devoid of the problematic hemiaminal stereocenter present in dolutegravir (DTG). This scaffold hopping made it easy to introduce several substituents, and evolving structure-activity studies using these scaffolds resulted in several leads with promising properties.
Assuntos
Desenho de Fármacos , Inibidores de Integrase de HIV , Integrase de HIV , HIV-1 , Piridonas , Humanos , Compostos Aza/química , Compostos Aza/farmacologia , Compostos Aza/síntese química , Relação Dose-Resposta a Droga , Integrase de HIV/metabolismo , Inibidores de Integrase de HIV/farmacologia , Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/síntese química , HIV-1/efeitos dos fármacos , Estrutura Molecular , Piridonas/química , Piridonas/farmacologia , Piridonas/síntese química , Relação Estrutura-Atividade , Integrases/química , Integrases/metabolismo , Integrases/farmacocinéticaRESUMO
Passage of HIV-1 in the presence of integrase inhibitors (INIs) generates resistant viruses that have mutations in the integrase region. Integrase-resistant mutations Q148K and Q148R were identified as primary mutations with the passage of HIV-1 IIIB in the presence of INIs S-1360 or S/GSK-364735, respectively. Secondary amino acid substitutions E138K or G140S were observed when passage with INI was continued. The role of these mutations was investigated with molecular clones. Relative to Q148K alone, Q148K/E138K had 2- and >6-fold increases in resistance to S-1360 and S/GSK-364735, respectively, and the double mutant had slightly better infectivity and replication kinetics. In contrast, Q148K/G140S and Q148R/E138K had nearly equivalent or slightly reduced fold resistance to the INI compared with their respective Q148 primary mutants, and had increases in infectivity and replication kinetics. Recovery of these surrogates of viral fitness coincided with the recovery of integration efficiency of viral DNA into the host cell chromosome for these double mutants. These data show that recovery of viral integration efficiency can be an important factor for the emergence and maintenance of INI-resistant mutations.
Assuntos
Fármacos Anti-HIV/farmacologia , Integrase de HIV/metabolismo , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Mutação de Sentido Incorreto , Replicação Viral/efeitos dos fármacos , Furanos/farmacologia , Integrase de HIV/genética , HIV-1/genética , Humanos , Células Jurkat , Triazóis/farmacologiaRESUMO
Resistance passage studies were conducted with five INIs (integrase inhibitors) that have been tested in clinical trials to date: a new naphthyridinone-type INI S/GSK-364735, raltegravir, elvitegravir, L-870,810 and S-1360. In establishing the passage system and starting from concentrations several fold above the EC(50) value, resistance mutations against S-1360 and related diketoacid-type compounds could be isolated from infected MT-2 cell cultures from day 14 to 28. Q148R and F121Y were the two main pathways of resistance to S/GSK-364735. Q148R/K and N155H, which were found in patients failing raltegravir treatment in Phase IIb studies, were observed during passage with raltegravir with this method. The fold resistance of 40 mutant molecular clones versus wild type virus was compared with these five INIs. The overall resistance pattern of S/GSK-364735 was similar to that of raltegravir and other INIs. However, different fold resistances of particular mutations were noted among different INIs, reflecting a potential to develop INIs with distinctly different resistant profiles.