Harnessing Nature’s Insight: Design of Aspartyl Protease Inhibitors from Treatment of Drug-Resistant HIV to Alzheimer’s Disease

Ghosh, Arun K.

doi:10.1021/jm900064c

Cited by 44 publications

(48 citation statements)

References 100 publications

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“…1 One of these inhibitors, darunavir ( 1 , K i = 16 pM, antiviral IC 50 = 4.1 nM, Figure 1) was first approved in June, 2006 for the treatment of HIV/AIDS patients harboring drug-resistant HIV-1 variants. 2 Later, darunavir recived an expanded approval for the treatment of all therapy-naïve HIV/AIDS patients includingpediatric patients.…”

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confidence: 99%

Design, Synthesis, and X-ray Structure of Substituted Bis-tetrahydrofuran (Bis-THF)-Derived Potent HIV-1 Protease Inhibitors

Ghosh

Martyr

Steffey

et al. 2011

ACS Med. Chem. Lett.

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We investigated substituted bis-THF-derived HIV-1 protease inhibitors in order to enhance ligand-binding site interactions in the HIV-1 protease active site. In this context, we have carried out convenient syntheses of optically active bis-THF and C4-substituted bis-THF ligands using a [2,3]-sigmatropic rearrangement as the key step. The synthesis provided convenient access to a number of substituted bis-THF derivatives. Incorporation of these ligands led to a series of potent HIV-1 protease inhibitors. Inhibitor 23c turned out to be the most potent (Ki = 2.9 pM; IC50 = 2.4 nM) among the inhibitors. An X-ray structure of 23c-bound HIV-1 protease showed extensive interactions of the inhibitor with the protease active site, including a unique water-mediated hydrogen bond to the Gly-48 amide NH in the S2 site.

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confidence: 99%

Design, Synthesis, and X-ray Structure of Substituted Bis-tetrahydrofuran (Bis-THF)-Derived Potent HIV-1 Protease Inhibitors

Ghosh

Martyr

Steffey

et al. 2011

ACS Med. Chem. Lett.

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“…Also, these PIs exhibited potent antiviral activity 3,12,13 against a panel of multidrug-resistant HIV-1 variants.…”

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confidence: 97%

Design of novel HIV-1 protease inhibitors incorporating isophthalamide-derived P2-P3 ligands: Synthesis, biological evaluation and X-ray structural studies of inhibitor-HIV-1 protease complex

Ghosh

Brindisi

Nyalapatla

et al. 2017

Bioorganic & Medicinal Chemistry

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Based upon molecular insights from the X-ray structures of inhibitor-bound HIV-1 protease complexes, we have designed a series of isophthalamide-derived inhibitors incorporating substituted pyrrolidines, piperidines and thiazolidines as P2-P3 ligands for specific interactions in the S2–S3 extended site. Compound 4b has shown an enzyme Ki of 0.025 nM and antiviral IC50 of 69 nM. An X-ray crystal structure of inhibitor 4b-HIV-1 protease complex was determined at 1.33 Å resolution. We have also determined X-ray structure of 3b-bound HIV-1 protease at 1.27 Å resolution. These structures revealed important molecular insight into the inhibitor–HIV-1 protease interactions in the active site.

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“…Indeed, it is typically found that incorporation of a secondary hydroxyl group enables access to this key interaction, although interestingly over the last 10 years amines have also been shown to play this role. 2–6 Accordingly the hydroxyl group is typically found on a poly-peptidic moiety linked together with different heterocycles. 2–3 In fact, the most well-known amide isosteres in this class are represented by hydroxyethylamines, hydroxyethylenes (mono or dihydroxy), statines, hydroxymethylenes and norstatines 1 .…”

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“…2–6 Accordingly the hydroxyl group is typically found on a poly-peptidic moiety linked together with different heterocycles. 2–3 In fact, the most well-known amide isosteres in this class are represented by hydroxyethylamines, hydroxyethylenes (mono or dihydroxy), statines, hydroxymethylenes and norstatines 1 . 2–5,7 This laboratory has recently been actively involved in the generation of conformationally constrained analogs of the latter norstatines, enabling entry into feasibly unique biologically active aspartic protease space.…”

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confidence: 99%

“…2–3 In fact, the most well-known amide isosteres in this class are represented by hydroxyethylamines, hydroxyethylenes (mono or dihydroxy), statines, hydroxymethylenes and norstatines 1 . 2–5,7 This laboratory has recently been actively involved in the generation of conformationally constrained analogs of the latter norstatines, enabling entry into feasibly unique biologically active aspartic protease space. On this theme, the rapid generation of libraries of cis -constrained norstatine analogs of general structure 2 using a TMSN 3 -modified Passerini/de-Boc/ N -capping protocol (a slight modification of the PADAM strategy used to produce libraries of 1 ) was reported in 2002 (Figure 1).…”

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Facile and rapid route for the synthesis of novel norstatine analogs via PADAM-cyclization methodology

Shaw

Medda

Hulme

2012

Tetrahedron Letters

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The following report describes novel methodology for the rapid synthesis of unique conformationally constrained norstatine analogs of potential biological relevance. A PADAM (Passerini reaction – Amine Deprotection – Acyl Migration reaction) sequence is followed by a TFA-mediated microwave-assisted cyclization to generate the final benzimidazole isostere of the norstatine scaffold in moderate to good yields. The applicability of this solution phase methodology to the preparation of a small collection of compounds is discussed.

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Harnessing Nature’s Insight: Design of Aspartyl Protease Inhibitors from Treatment of Drug-Resistant HIV to Alzheimer’s Disease

Cited by 44 publications

References 100 publications

Design, Synthesis, and X-ray Structure of Substituted Bis-tetrahydrofuran (Bis-THF)-Derived Potent HIV-1 Protease Inhibitors

Design, Synthesis, and X-ray Structure of Substituted Bis-tetrahydrofuran (Bis-THF)-Derived Potent HIV-1 Protease Inhibitors

Design of novel HIV-1 protease inhibitors incorporating isophthalamide-derived P2-P3 ligands: Synthesis, biological evaluation and X-ray structural studies of inhibitor-HIV-1 protease complex

Facile and rapid route for the synthesis of novel norstatine analogs via PADAM-cyclization methodology

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