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PDBsum entry 3o9f
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Hydrolase/hydrolase inhibitor
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PDB id
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3o9f
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References listed in PDB file
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Key reference
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Title
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Substrate envelope-Designed potent HIV-1 protease inhibitors to avoid drug resistance.
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Authors
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M.N.Nalam,
A.Ali,
G.S.Reddy,
H.Cao,
S.G.Anjum,
M.D.Altman,
N.K.Yilmaz,
B.Tidor,
T.M.Rana,
C.A.Schiffer.
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Ref.
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Chem Biol, 2013,
20,
1116-1124.
[DOI no: ]
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PubMed id
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Abstract
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The rapid evolution of HIV under selective drug pressure has led to multidrug
resistant (MDR) strains that evade standard therapies. We designed highly potent
HIV-1 protease inhibitors (PIs) using the substrate envelope model, which
confines inhibitors within the consensus volume of natural substrates, providing
inhibitors less susceptible to resistance because a mutation affecting such
inhibitors will simultaneously affect viral substrate processing. The designed
PIs share a common chemical scaffold but utilize various moieties that optimally
fill the substrate envelope, as confirmed by crystal structures. The designed
PIs retain robust binding to MDR protease variants and display exceptional
antiviral potencies against different clades of HIV as well as a panel of 12
drug-resistant viral strains. The substrate envelope model proves to be a
powerful strategy to develop potent and robust inhibitors that avoid drug
resistance.
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