title: Novel HIV-1 protease inhibitors (PIs) containing a bicyclic P2 functional moiety, tetrahydropyrano-tetrahydrofuran, that are potent against multi-PI-resistant HIV-1 variants.
abstract: We identified GRL-1388 and -1398, potent nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) containing a bicyclic P2 functional moiety, tetrahydropyrano-tetrahydrofuran (Tp-THF). GRL-1388 was as potent as darunavir (DRV) against various drug-resistant HIV-1 laboratory strains with 50% effective concentration (EC(50)s) of 2.6 to 32.6 nM. GRL-1398 was significantly more potent against such variants than DRV with EC(50)s of 0.1 to 5.7 nM. GRL-1388 and -1398 were also potent against multiple-PI-resistant clinical HIV-1 variants ((CL)HIV-1(MDR)) with EC(50)s ranging from 2.7 to 21.3 nM and from 0.3 to 4.8 nM, respectively. A highly DRV-resistant HIV-1 variant selected in vitro remained susceptible to GRL-1398 with the EC(50) of 21.9 nM, while the EC(50) of DRV was 214.1 nM. When HIV-1(NL4-3) was selected with GRL-1398, four amino acid substitutions--leucine to phenylalanine at a position 10 (L10F), A28S, L33F, and M46I--emerged, ultimately enabling the virus to replicate in the presence of >1.0 μM the compound beyond 57 weeks of selection. When a mixture of 10 different (CL)HIV-1(MDR) strains was selected, the emergence of resistant variants was more substantially delayed with GRL-1398 than with GRL-1388 and DRV. Modeling analyses revealed that GRL-1398 had greater overall hydrogen bonding and hydrophobic interactions than GRL-1388 and DRV and that GRL-1388 and -1398 had hydrogen bonding interactions with the main chain of the active-site amino acids (Asp29 and Asp30) of protease. The present findings warrant that GRL-1398 be further developed as a potential drug for treating individuals with HIV-1 infection.
authors.affiliation: Department of Hematology, Kumamoto University School of Medicine, Kumamoto 860-8556, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Ide
authors.forename: Manabu
authors.initials: M
authors.lastname: Aoki
authors.forename: Masayuki
authors.initials: M
authors.lastname: Amano
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Koh
authors.forename: Ravikiran S
authors.initials: RS
authors.lastname: Yedidi
authors.forename: Debananda
authors.initials: D
authors.lastname: Das
authors.forename: Sofiya
authors.initials: S
authors.lastname: Leschenko
authors.forename: Bruno
authors.initials: B
authors.lastname: Chapsal
authors.forename: Arun K
authors.initials: AK
authors.lastname: Ghosh
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mitsuya
mesh_terms: D000818:Animals; D019556:COS Cells; D002219:Carbamates / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002522:Chlorocebus aethiops; D024882:Drug Resistance, Viral; D005663:Furans / Q000737:chemistry*; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D011714:Pyrans / Q000737:chemistry*; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology
chemical_list: D002219:Carbamates; D005663:Furans; D017320:HIV Protease Inhibitors; D011714:Pyrans; D013449:Sulfonamides; C018674:tetrahydrofuran; C095108:amprenavir