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Publication Abstract from PubMed

We identified three non-peptidic HIV-1 protease inhibitors (PIs), GRL-015, -085, and -097 containing tetrahydropyrano-tetrahydrofuran (Tp-THF) with a C5 hydroxyl. The three compounds were potent against a wild-type laboratory HIV-1 strain (HIV-1WT) with 50% effective concentrations (EC50s) of 3.0-49 nM and minimal cytotoxicity with 50% cytotoxic concentrations (CC50) for GRL-015, -085, and -097 of 80, >100, and >100 muM, 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 multi-drug 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 to HIV-1DRV R P51 only with 6.8- to 68-fold reduction. Moreover, the emergence of drug resistant HIV-1s against the three compounds was considerably delayed compared to the case of DRV. Especially, HIV-1 variants resistant to GRL-085 and -097 did not emerge even by using two different highly-DRV-resistant HIV-1s 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 warrant that the three compounds be further studied as possible therapeutic agents for treating individuals harboring wild-type and/or HIVMDR. IMPORTANCE: Darunavir (DRV) inhibits the replication of most existing multidrug-resistant HIV-1s and has a high genetic barrier. However, the emergence of highly DRV-resistant HIV-1s (HIVDRV R) has recently been reported in vivo and in vitro. Here we identified three novel HIV-1 protease inhibitors (PIs) containing a tetrahydropyrano-tetrahydrofuran (Tp-THF) moiety with a C5 hydroxyl (GRL-015, -085, and -097), which potently suppress the replication of HIVDRV R. Moreover, the emergence of drug resistant HIV-1s against the three compounds was considerably delayed compared to the case of DRV. The C5 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 the activity against HIVDRV Rs. 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.

The C5-substituted Tetrahydropyrano-tetrahydofuran-derived Protease Inhibitors (PIs) Exert Potent Inhibition of the Replication of HIV-1 Variants Highly Resistant to Various PIs Including Darunavir.,Aoki M, Hayashi H, Yedidi RS, Martyr CD, Takamatsu Y, Aoki-Ogata H, Nakamura T, Nakata H, Das D, Yamagata Y, Ghosh AK, Mitsuya H J Virol. 2015 Nov 18. pii: JVI.01829-15. PMID:26581995^[1]

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