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Similarly, GRL-09510 efficiently blocked the replication of HIV-1<jats:sub>NL4-3<\/jats:sub> variants, which were capable of propagating at high-concentrations of atazanavir, lopinavir, and amprenavir (APV). GRL-09510 was also potent against multi-drug-resistant clinical HIV-1 variants and HIV-2<jats:sub>ROD<\/jats:sub>. Under the selection condition, where HIV-1<jats:sub>NL4-3<\/jats:sub> rapidly acquired significant resistance to APV, an integrase inhibitor raltegravir, and a GRL-09510 congener (GRL-09610), no variants highly resistant against GRL-09510 emerged over long-term <jats:italic>in vitro<\/jats:italic> passage of the virus. Crystallographic analysis demonstrated that the <jats:italic>Crwn<\/jats:italic>-THF moiety of GRL-09510 forms strong hydrogen-bond-interactions with HIV-1 protease (PR) active-site amino acids and is bulkier with a larger contact surface, making greater van der Waals contacts with PR than the <jats:italic>bis<\/jats:italic>-THF moiety of darunavir. The present data demonstrate that GRL-09510 has favorable features for treating patients infected with wild-type and\/or multi-drug-resistant HIV-1 variants, that the newly generated P2-<jats:italic>Crwn<\/jats:italic>-THF moiety confers highly desirable anti-HIV-1 potency. The use of the novel <jats:italic>Crwn<\/jats:italic>-THF moiety sheds lights in the design of novel PIs.<\/jats:p>","DOI":"10.1038\/s41598-017-12052-9","type":"journal-article","created":{"date-parts":[[2017,9,19]],"date-time":"2017-09-19T08:23:49Z","timestamp":1505809429000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["GRL-09510, a Unique P2-Crown-Tetrahydrofuranylurethane -Containing HIV-1 Protease Inhibitor, Maintains Its Favorable Antiviral Activity against Highly-Drug-Resistant HIV-1 Variants in vitro"],"prefix":"10.1038","volume":"7","author":[{"given":"Masayuki","family":"Amano","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedro","family":"Miguel Salcedo-G\u00f3mez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ravikiran S.","family":"Yedidi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole S.","family":"Delino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirotomo","family":"Nakata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kalapala","family":"Venkateswara Rao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arun K.","family":"Ghosh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroaki","family":"Mitsuya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,9,25]]},"reference":[{"key":"12052_CR1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1001044","volume":"8","author":"A Edmonds","year":"2011","unstructured":"Edmonds, A. et al. 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