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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 ?M 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.

SUBMITTER: Ide K

PROVIDER: S-EPMC3067155 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Novel HIV-1 protease inhibitors (PIs) containing a bicyclic P2 functional moiety, tetrahydropyrano-tetrahydrofuran, that are potent against multi-PI-resistant HIV-1 variants.

Ide Kazuhiko K Aoki Manabu M Amano Masayuki M Koh Yasuhiro Y Yedidi Ravikiran S RS Das Debananda D Leschenko Sofiya S Chapsal Bruno B Ghosh Arun K AK Mitsuya Hiroaki H

Antimicrobial agents and chemotherapy 20110131 4

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 ...[more]

PMID: 21282450

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Project description:UNLABELLED:We identified three nonpeptidic HIV-1 protease inhibitors (PIs), GRL-015, -085, and -097, containing tetrahydropyrano-tetrahydrofuran (Tp-THF) with a C-5 hydroxyl. The three compounds were potent against a wild-type laboratory HIV-1 strain (HIV-1(WT)), with 50% effective concentrations (EC50s) of 3.0 to 49 nM, and exhibited minimal cytotoxicity, with 50% cytotoxic concentrations (CC50) for GRL-015, -085, and -097 of 80, >100, and >100 ?M, respectively. All the three compounds potently inhibited the replication of highly PI-resistant HIV-1 variants selected with each of the currently available PIs and recombinant clinical HIV-1 isolates obtained from patients harboring multidrug-resistant HIV-1 variants (HIVMDR). Importantly, darunavir (DRV) was >1,000 times less active against a highly DRV-resistant HIV-1 variant (HIV-1DRV(R) P51); the three compounds remained active against HIV-1DRV(R) P51 with only a 6.8- to 68-fold reduction. Moreover, the emergence of HIV-1 variants resistant to the three compounds was considerably delayed compared to the case of DRV. In particular, HIV-1 variants resistant to GRL-085 and -097 did not emerge even when two different highly DRV-resistant HIV-1 variants were used as a starting population. In the structural analyses, Tp-THF of GRL-015, -085, and -097 showed strong hydrogen bond interactions with the backbone atoms of active-site amino acid residues (Asp29 and Asp30) of HIV-1 protease. A strong hydrogen bonding formation between the hydroxyl moiety of Tp-THF and a carbonyl oxygen atom of Gly48 was newly identified. The present findings indicate that the three compounds warrant further study as possible therapeutic agents for treating individuals harboring wild-type HIV and/or HIVMDR. IMPORTANCE:Darunavir (DRV) inhibits the replication of most existing multidrug-resistant HIV-1 strains and has a high genetic barrier. However, the emergence of highly DRV-resistant HIV-1 strains (HIVDRV(R) ) has recently been observed in vivo and in vitro. Here, we identified three novel HIV-1 protease inhibitors (PIs) containing a tetrahydropyrano-tetrahydrofuran (Tp-THF) moiety with a C-5 hydroxyl (GRL-015, -085, and -097) which potently suppress the replication of HIVDRV(R) . Moreover, the emergence of HIV-1 strains resistant to the three compounds was considerably delayed compared to the case of DRV. The C-5 hydroxyl formed a strong hydrogen bonding interaction with the carbonyl oxygen atom of Gly48 of protease as examined in the structural analyses. Interestingly, a compound with Tp-THF lacking the hydroxyl moiety substantially decreased activity against HIVDRV(R) . The three novel compounds should be further developed as potential drugs for treating individuals harboring wild-type and multi-PI-resistant HIV variants as well as HIVDRV(R) .

Dataset Information

Novel HIV-1 protease inhibitors (PIs) containing a bicyclic P2 functional moiety, tetrahydropyrano-tetrahydrofuran, that are potent against multi-PI-resistant HIV-1 variants.

Publications

Novel HIV-1 protease inhibitors (PIs) containing a bicyclic P2 functional moiety, tetrahydropyrano-tetrahydrofuran, that are potent against multi-PI-resistant HIV-1 variants.

Similar Datasets

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