1ody: Difference between revisions

Revision as of 15:16, 21 February 2008

HIV-1 PROTEASE COMPLEXED WITH AN INHIBITOR LP-130

OverviewOverview

One of the major problems encountered in antiviral therapy against AIDS is the emergence of viral variants that exhibit drug resistance. The sequences of proteases (PRs) from related retroviruses sometimes include, at structurally equivalent positions, amino acids identical to those found in drug-resistant forms of HIV-1 PR. The statine-based inhibitor LP-130 was found to be a universal, nanomolar-range inhibitor against all tested retroviral PRs. We solved the crystal structures of LP-130 in complex with retroviral PRs from HIV-1, feline immunodeficiency virus, and equine infectious anemia virus and compared the structures to determine the differences in the interactions between the inhibitor and the active-site residues of the enzymes. This comparison shows an extraordinary similarity in the binding modes of the inhibitor molecules. The only exceptions are the different conformations of naphthylalanine side chains at the P3/P3' positions, which might be responsible for the variation in the Ki values. These findings indicate that successful inhibition of different retroviral PRs by LP-130 is achieved because this compound can be accommodated without serious conformational differences, despite the variations in the type of residues forming the active-site region. Although strong, specific interactions between the ligand and the enzyme might improve the potency of the inhibitor, the absence of such interactions seems to favor the universality of the compound. Hence, the ability of potential anti-AIDS drugs to inhibit multiple retroviral PRs might indicate their likelihood of not eliciting drug resistance. These studies may also contribute to the development of a small-animal model for preclinical testing of antiviral compounds.

About this StructureAbout this Structure

1ODY is a Single protein structure of sequence from Human immunodeficiency virus type 1 (isolate hxb2) with as ligand. Active as HIV-1 retropepsin, with EC number 3.4.23.16 Full crystallographic information is available from OCA.

ReferenceReference

Toward a universal inhibitor of retroviral proteases: comparative analysis of the interactions of LP-130 complexed with proteases from HIV-1, FIV, and EIAV., Kervinen J, Lubkowski J, Zdanov A, Bhatt D, Dunn BM, Hui KY, Powell DJ, Kay J, Wlodawer A, Gustchina A, Protein Sci. 1998 Nov;7(11):2314-23. PMID:9827997

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 ==Overview==
-One of the major problems encountered in antiviral therapy against AIDS is, the emergence of viral variants that exhibit drug resistance. The, sequences of proteases (PRs) from related retroviruses sometimes include, at structurally equivalent positions, amino acids identical to those found, in drug-resistant forms of HIV-1 PR. The statine-based inhibitor LP-130, was found to be a universal, nanomolar-range inhibitor against all tested, retroviral PRs. We solved the crystal structures of LP-130 in complex with, retroviral PRs from HIV-1, feline immunodeficiency virus, and equine, infectious anemia virus and compared the structures to determine the, differences in the interactions between the inhibitor and the active-site, residues of the enzymes. This comparison shows an extraordinary similarity, in the binding modes of the inhibitor molecules. The only exceptions are, the different conformations of naphthylalanine side chains at the P3/P3', positions, which might be responsible for the variation in the Ki values., These findings indicate that successful inhibition of different retroviral, PRs by LP-130 is achieved because this compound can be accommodated, without serious conformational differences, despite the variations in the, type of residues forming the active-site region. Although strong, specific, interactions between the ligand and the enzyme might improve the potency, of the inhibitor, the absence of such interactions seems to favor the, universality of the compound. Hence, the ability of potential anti-AIDS, drugs to inhibit multiple retroviral PRs might indicate their likelihood, of not eliciting drug resistance. These studies may also contribute to the, development of a small-animal model for preclinical testing of antiviral, compounds.
+One of the major problems encountered in antiviral therapy against AIDS is the emergence of viral variants that exhibit drug resistance. The sequences of proteases (PRs) from related retroviruses sometimes include, at structurally equivalent positions, amino acids identical to those found in drug-resistant forms of HIV-1 PR. The statine-based inhibitor LP-130 was found to be a universal, nanomolar-range inhibitor against all tested retroviral PRs. We solved the crystal structures of LP-130 in complex with retroviral PRs from HIV-1, feline immunodeficiency virus, and equine infectious anemia virus and compared the structures to determine the differences in the interactions between the inhibitor and the active-site residues of the enzymes. This comparison shows an extraordinary similarity in the binding modes of the inhibitor molecules. The only exceptions are the different conformations of naphthylalanine side chains at the P3/P3' positions, which might be responsible for the variation in the Ki values. These findings indicate that successful inhibition of different retroviral PRs by LP-130 is achieved because this compound can be accommodated without serious conformational differences, despite the variations in the type of residues forming the active-site region. Although strong, specific interactions between the ligand and the enzyme might improve the potency of the inhibitor, the absence of such interactions seems to favor the universality of the compound. Hence, the ability of potential anti-AIDS drugs to inhibit multiple retroviral PRs might indicate their likelihood of not eliciting drug resistance. These studies may also contribute to the development of a small-animal model for preclinical testing of antiviral compounds.
 ==About this Structure==
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 [[Category: retrovirus]]
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+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:16:43 2008''