A Conserved Hydrogen-Bonding Network of P2
            <i>bis</i>
            -Tetrahydrofuran-Containing HIV-1 Protease Inhibitors (PIs) with a Protease Active-Site Amino Acid Backbone Aids in Their Activity against PI-Resistant HIV

Yedidi, Ravikiran S.; Garimella, Harisha; Aoki, Manabu; Aoki-Ogata, Hiromi; Desai, Darshan V.; Chang, Simon B.; Davis, David A.; Fyvie, W. Sean; Kaufman, Joshua D.; Smith, David W.; Das, Debananda; Wingfield, Paul T.; Maeda, Kenji; Ghosh, Arun K.; Mitsuya, Hiroaki

doi:10.1128/aac.00107-14

Cited by 18 publications

(18 citation statements)

References 38 publications

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“…80 Inhibitor 12 displayed excellent retention of affinity against the mutant proteases with 0.8- and 2.6-fold changes. A crystal structure was solved for 12 -bound PR A02 mutant protease to help elucidate the results of the cellular binding assay (Figure 9).…”

Section: (5) Recent Progress Towards Hiv-1 Protease Inhibitorsmentioning

confidence: 99%

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Recent Progress in the Development of HIV-1 Protease Inhibitors for the Treatment of HIV/AIDS

2016

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HIV-1 protease inhibitors continue to play an important role in the treatment of HIV/AIDS, transforming this deadly ailment into a more manageable chronic infection. Over the years, intensive research led to a variety of approved protease inhibitors for the treatment of HIV/AIDS. In this review, we outline current drug design and medicinal chemistry efforts toward the development of new generation protease inhibitors beyond the currently approved drugs.

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Section: (5) Recent Progress Towards Hiv-1 Protease Inhibitorsmentioning

confidence: 99%

“…This interaction was absent with darunavir, which may explain the observed difference in potency. 80 …”

Section: (5) Recent Progress Towards Hiv-1 Protease Inhibitorsmentioning

confidence: 99%

Recent Progress in the Development of HIV-1 Protease Inhibitors for the Treatment of HIV/AIDS

2016

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“…The structure also forms weaker hydrogen bonds to the backbone of conserved residues Asp29, Asp30/30’. A later study revealed that GRL-008 maintained wild-type polar interactions in the active site of a highly mutated protease from a clinical isolate [66]. It is noteworthy that DRV also conserves polar bonding with the same mutant and outperformed GRL-008 in antiviral activity against wild type and resistant strains.…”

Section: Investigational Antiviral Inhibitorsmentioning

confidence: 99%

Highly Resistant HIV-1 Proteases and Strategies for Their Inhibition

2015

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The virally encoded protease is an important drug target for AIDS therapy. Despite the potency of the current drugs, infections with resistant viral strains limit the long-term effectiveness of therapy. Highly resistant variants of HIV protease from clinical isolates have different combinations of about 20 mutations and several orders of magnitude worse binding affinity for clinical inhibitors. Strategies are being explored to inhibit these highly resistant mutants. The existing inhibitors can be modified by introducing groups with the potential to form new interactions with conserved protease residues, and the flexible flaps. Alternative strategies are discussed, including designing inhibitors to bind to the open conformation of the protease dimer, and inhibition of the protease-catalyzed processing of the Gag-Pol precursor.

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“…Structure solutions were obtained using the molecular replacement (MR) method as described previously (36,37). Briefly, MR was performed using MOLREP (38) through the CCP4 (39,40) interface with WT PR taken from PDB ID 4HLA as a search model.…”

Section: Cells and Virusesmentioning

confidence: 99%

C-5-Modified Tetrahydropyrano-Tetrahydofuran-Derived Protease Inhibitors (PIs) Exert Potent Inhibition of the Replication of HIV-1 Variants Highly Resistant to Various PIs, including Darunavir

Aoki

Hayashi

Yedidi

et al. 2016

J Virol

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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 (EC 50 s) of 3.0 to 49 nM, and exhibited minimal cytotoxicity, with 50% cytotoxic concentrations (CC 50 ) for GRL-015, -085, and -097 of 80, >100, and >100 M,

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A Conserved Hydrogen-Bonding Network of P2 bis -Tetrahydrofuran-Containing HIV-1 Protease Inhibitors (PIs) with a Protease Active-Site Amino Acid Backbone Aids in Their Activity against PI-Resistant HIV

Cited by 18 publications

References 38 publications

Recent Progress in the Development of HIV-1 Protease Inhibitors for the Treatment of HIV/AIDS

Recent Progress in the Development of HIV-1 Protease Inhibitors for the Treatment of HIV/AIDS

Highly Resistant HIV-1 Proteases and Strategies for Their Inhibition

C-5-Modified Tetrahydropyrano-Tetrahydofuran-Derived Protease Inhibitors (PIs) Exert Potent Inhibition of the Replication of HIV-1 Variants Highly Resistant to Various PIs, including Darunavir

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