In VitroAntiretroviral Properties of S/GSK1349572, a Next-Generation HIV Integrase Inhibitor

Abstract

S/GSK1349572 is a next-generation HIV integrase (IN) inhibitor designed to deliver potent antiviral activity with a low-milligram once-daily dose requiring no pharmacokinetic (PK) booster. In addition, S/GSK1349572 demonstrates activity against clinically relevant IN mutant viruses and has potential for a high genetic barrier to resistance. S/GSK1349572 is a two-metal-binding HIV integrase strand transfer inhibitor whose mechanism of action was established through in vitro integrase enzyme assays, resistance passage experiments, activity against viral strains resistant to other classes of anti-HIV agents, and mechanistic cellular assays. In a variety of cellular antiviral assays, S/GSK1349572 inhibited HIV replication with low-nanomolar or subnanomolar potency and with a selectivity index of 9,400. The protein-adjusted half-maximal effective concentration (PA-EC 50 ) extrapolated to 100% human serum was 38 nM. When virus was passaged in the presence of S/GSK1349572, highly resistant mutants were not selected, but mutations that effected a low fold change (FC) in the EC 50 (up to 4.1 fold) were identified in the vicinity of the integrase active site. S/GSK1349572 demonstrated activity against site-directed molecular clones containing the raltegravir-resistant signature mutations Y143R, Q148K, N155H, and G140S/Q148H (FCs, 1.4, 1.1, 1.2, and 2.6, respectively), while these mutants led to a high FC in the EC 50 of raltegravir (11-to >130-fold). Either additive or synergistic effects were observed when S/GSK1349572 was tested in combination with representative approved antiretroviral agents; no antagonistic effects were seen. These findings demonstrate that S/GSK1349572 would be classified as a nextgeneration drug in the integrase inhibitor class, with a resistance profile markedly different from that of first-generation integrase inhibitors.Twenty-three compounds are currently approved for the treatment of HIV infection. These drugs can be assigned to six classes: nucleoside (nucleotide) reverse transcriptase inhibitors [N(t)RTIs], nonnucleoside reverse transcriptase inhibitors [NNRTIs], protease inhibitors [PIs], integrase inhibitors [INIs], CCR5 antagonists, and fusion inhibitors. The development of resistance to all currently marketed drugs has been observed and is a major reason for failure of therapy. Thus, the development of new, potent antiretroviral compounds with different resistance profiles and mechanisms of action is urgently needed for patients who have multidrugresistant HIV. In addition to these characteristics, an improved side effect profile and improved dosing convenience (oncedaily dosing, fixed-dose combination pills) are desirable, because they would promote high compliance, decrease the emergence of drug-resistant variants, and thus enhance the length and quality of life.After an initial period of false starts, advances in the field of HIV integrase drug discovery since the late 1990s have been outstanding. Beginning with the discovery that molecules capable of binding two metals within the int...

Characterization of the Drug Resistance Profiles of Integrase Strand Transfer Inhibitors in Simian Immunodeficiency Virus SIVmac239

“…While resistance mutations were detected within 29 weeks under either DTG or EVG selection pressure, no resistance mutations emerged under pressure with RAL. A direct comparison cannot be drawn between our selection studies, which were performed using rhesus PBMCs, and those performed by others who used HIV-1 in MT-2 cell lines and showed that mutations emerged rapidly under RAL pressure (31,46). Our selection experiments with RAL may suggest that RAL possesses a higher genetic barrier than the other INSTIs in rhesus macaques; however, a previous study revealed that SHIV-infected macaques treated with pressure from L-870812, a RAL analogue, possessed the N155H substitution after 25 days of treatment with this drug (36).…”

“…Viruses under RAL selective pressure did not select for any substitutions. E92Q is the most frequent substitution in HIV-1-infected individuals treated with EVG (28-30) and confers high levels of resistance against this compound (31).…”

Might dolutegravir be part of a functional cure for HIV?

“…Some mutations in integrase that are potentially involved in resistance to DTG were reported at positions F121, S153, G118, E138, and R263 in vitro and in vivo (Kobayashi et al 2011;Quashie et al 2013b). R263K was initially reported as the most common substitution identified in cell culture selections with DTG and was shown to confer only moderate resistance to DTG (fold change = 2.3-fold) (Quashie et al 2012).…”

Dolutegravir: clinical efficacy and role in HIV therapy

“…These properties are probably responsible for the effectiveness of DTG against most RAL/EVG resistant strains, although viruses containing E138K, G140S or Q148H mutations had lower susceptibility [Quashie et al 2012b]. Exposure to DTG in selection studies can cause changes in the viral genome at positions E92, L101, T124, S153 and G193 [Kobayashi et al 2011]. However, susceptibility fold changes are moderate (<2.5) for all these substitutions.…”