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Publication Abstract from PubMed

We newly generated two nonpeptidic HIV-1 protease inhibitors (PIs), GRL-001-15 and GRL-003-15, which contain a unique P2-crown-THF (Crn-THF) and P2'-cyclopropyl-amino-benzothiazole (Cp-Abt) moieties. GRL-001-15 and GRL-003-15 have meta-mono-fluorophenyl and para-mono-fluorophenyl at the P1 site, exert highly potent activity against wild-type HIV-1 with 50% effective concentrations (EC50s) of 57 and 50 pM, and have favorable cytotoxicity profiles with 50% cytotoxic concentrations (CC50s) of 38 and 11 muM, respectively. The activity of GRL-001-15 against multi-PI-resistant HIV-1 variants was generally greater than that of GRL-003-15. The EC50 value of GRL-001-15 against an HIV-1 variant highly resistant to multiple PIs including darunavir (DRV) (HIV-1DRV (R) P30) was 0.17 nM and that of GRL-003-15 was 3.3 nM, while DRV was much less active with an EC50 value of 216 nM. The emergence of HIV-1 variants resistant to GRL-001-15 and GRL-003-15 was significantly delayed compared to that of selected PIs including DRV. Structural analyses of wild-type protease (PR(WT)) complexed with the novel PIs revealed that GRL-001-15's meta-fluorine atom forms halogen bond interactions (2.9 and 3.0 A) with Gly49 and Ile50, respectively, of the protease flap region and Pro81' (2.7 and 3.2 A) located close to the protease active site; and that two fluorine atoms of GRL-142-13 form multiple halogen bond interactions with Gly49, Ile50, Pro81', Ile82', and Arg8'. In contrast, GRL-003-15 forms halogen bond interactions with Pro81' alone, suggesting that the reduced antiviral activity of GRL-003-15 is due to the loss of the interactions with the flap region.

Halogen bond interactions of novel HIV-1 protease inhibitors (PI)(GRL-001-15 and GRL-003-15) with the flap of protease are critical for their potent activity against wild-type and multi-PI-resistant HIV-1 variants.,Hattori SI, Hayashi H, Bulut H, Rao KV, Nyalapatla PR, Hasegawa K, Aoki M, Ghosh AK, Mitsuya H Antimicrob Agents Chemother. 2019 Apr 8. pii: AAC.02635-18. doi:, 10.1128/AAC.02635-18. PMID:30962341^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.