A potent and orally active HIV-1 integrase inhibitor

Egbertson, Melissa S.; Moritz, H.; Melamed, Jeffrey Y.; Han, Wei; Perlow, Debra S.; Kuo, Michelle S.; Embrey, Mark W.; Vacca, Joseph P.; Zrada, Matthew M.; Cortes, Amanda R.; Wallace, Audrey A.; Leonard, Yvonne; Hazuda, Daria J.; Miller, Michael D.; Felock, Peter J.; Stillmock, Kara A.; Witmer, Marc; Schleif, William A.; Gabryelski, Lori J.; Moyer, Gregory; Ellis, Joan D.; Jin, Lixia; Xu, Wujie; Braun, Matthew P.; Kassahun, Kellem; Tsou, Nancy N.; Young, Steven D.

doi:10.1016/j.bmcl.2006.11.080

Cited by 30 publications

(28 citation statements)

References 9 publications

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“…The search for effective HIV integrase inhibitors has been long and frustrating but punctuated with recent success [29]. The key was to look for inhibitors of "strand transfer" in the integration reaction, not the initial binding of integrase to DNA.…”

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confidence: 99%

A history of AIDS: Looking back to see ahead

Greene

2007

Eur. J. Immunol.

136

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confidence: 99%

A history of AIDS: Looking back to see ahead

Greene

2007

Eur. J. Immunol.

136

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“…To further our understanding of INSTI binding, we refined structures of PFV intasomes bound to Mg 2+ , the physiological cofactor, and eight small-molecule inhibitors representing six distinct INSTI scaffolds ( Fig. 1): raltegravir (14), L-870,810 (13), PICA (27), GS9160 (28), MK0536 (29), MK2048 (30), 1 (30), and 2 (31). HIV-1 resistance profiles for most of these INSTIs or their close analogs have been reported (20,(32)(33)(34)(35)(36)(37).…”

Section: Resultsmentioning

confidence: 99%

“…10 and 11). All INSTIs described to date are structurally related to the predecessor diketo acid and naphthyridine carboxamide scaffolds (12,13). Raltegravir, the first INSTI approved for clinical use, has demonstrated the great therapeutic promise of this class of antiretrovirals (14).…”

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confidence: 99%

Molecular mechanisms of retroviral integrase inhibition and the evolution of viral resistance

Hare

Vos²,

Clayton³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

277

394

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The development of HIV integrase (IN) strand transfer inhibitors (INSTIs) and our understanding of viral resistance to these molecules have been hampered by a paucity of available structural data. We recently reported cocrystal structures of the prototype foamy virus (PFV) intasome with raltegravir and elvitegravir, establishing the general INSTI binding mode. We now present an expanded set of cocrystal structures containing PFV intasomes complexed with firstand second-generation INSTIs at resolutions of up to 2.5 Å. Importantly, the improved resolution allowed us to refine the complete coordination spheres of the catalytic metal cations within the INSTIbound intasome active site. We show that like the Q148H/G140S and N155H HIV-1 IN variants, the analogous S217H and N224H PFV INs display reduced sensitivity to raltegravir in vitro. Crystal structures of the mutant PFV intasomes in INSTI-free and -bound forms revealed that the amino acid substitutions necessitate considerable conformational rearrangements within the IN active site to accommodate an INSTI, thus explaining their adverse effects on raltegravir antiviral activity. Furthermore, our structures predict physical proximity and an interaction between HIV-1 IN mutant residues His148 and Ser/Ala140, rationalizing the coevolution of Q148H and G140S/ A mutations in drug-resistant viral strains.

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“…Beginning with the discovery that molecules capable of binding two metals within the integrase active site can potently inhibit the recombinant enzyme and virus replication in cells (17), many INIs with different chemical scaffolds have proceeded from preclinical to clinical development (e.g., S-1360 [4], L-870,810 [14], S/GSK364735 [15], GS-9160 [22], raltegravir [RAL, MK-0518] [30,31], and elvitegravir [EVG, GS-9137] [13,43]). RAL was approved by the U.S. FDA in 2007, while EVG has progressed into phase 3 development at the time of this writing.…”

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confidence: 99%

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

Kobayashi

Yoshinaga

Seki

et al. 2011

Antimicrob Agents Chemother

353

337

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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...

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A potent and orally active HIV-1 integrase inhibitor

Cited by 30 publications

References 9 publications

A history of AIDS: Looking back to see ahead

A history of AIDS: Looking back to see ahead

Molecular mechanisms of retroviral integrase inhibition and the evolution of viral resistance

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

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