Comparative analysis of the X-ray structures of HIV-1 and HIV-2 proteases in complex with CGP 53820, a novel pseudosymmetric inhibitor

Priestle, John P.; Fässler, Alexander; Rösel, Johannes; Tintelnot‐Blomley, Marina; Štrop, Petr; Grütter, M.G.

doi:10.1016/s0969-2126(01)00169-1

Cited by 65 publications

(91 citation statements)

References 40 publications

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“…Although they have similar structures (40), HIV-2 and HIV-1 proteases are approximately 50% divergent in their amino acid compositions (21). Moreover, differences in conformation (32) and interaction parameters with substrates or PI have been described (15,29,43). It is important to know if natural polymorphism and mutations which confer resistance to PI in HIV-1 are found at homologous positions in the HIV-2 protease.…”

Section: Discussionmentioning

confidence: 99%

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Polymorphism and Drug-Selected Mutations in the Protease Gene of Human Immunodeficiency Virus Type 2 from Patients Living in Southern France

et al. 2004

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The susceptibility of human immunodeficiency virus type 2 (HIV-2) to protease inhibitors (PI) is largely unknown. We studied HIV-2 protease genes from 21 HIV-2-infected patients who were exposed or not exposed to PI. The aim of this study was (i) to characterize the polymorphism of HIV-2 protease in the absence of drug, (ii) to know whether the HIV-2 protease gene naturally harbors HIV-1 drug resistance codons, and (iii) to identify mutations emerging under PI-selective pressure. Sixty-five HIV-2 RNA or proviral DNA samples were directly sequenced from the plasma or peripheral blood mononuclear cells of 8 patients who had received PI and 13 patients who had never received any antiretroviral. In untreated patients, the highest amino acid variability in HIV-2 protease was observed at positions 14, 40, 43, 46, 65 and 70, and seven codons (10V, 32I, 36I, 46I, 47V, 71V, and 73A) associated with drug resistance in HIV-1 were highly prevalent. In addition, at six positions (positions 7, 46, 62, 71, 90, and 99), the amino acid variability or the amino acid frequencies or both differed significantly in PI-treated and untreated patients, suggesting that mutations 7K3R, 46V3I, 62V3A/T, 71V3I, 90L3M and 99L3F were occurring under PI-selective pressure. At these positions, at least one sample simultaneously harbored both wild-type and mutated codons, while substitutions at positions 62, 71, 90, and 99 were confirmed in a longitudinal analysis. Moreover, the presence of codons 46I and 99F in the absence of drug in HIV-2 subtype B proteases may reflect natural resistance to PI. In conclusion, the present study revealed that HIV-2 strains harbor specific patterns of natural polymorphism and resistance.

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Section: Discussionmentioning

confidence: 99%

“…Strategies, abstr. 32,2002). To date, only one study has reported the presence of genotypic changes in the protease gene of HIV-2 which could be drug resistance-associated mutations (34).…”

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confidence: 99%

Polymorphism and Drug-Selected Mutations in the Protease Gene of Human Immunodeficiency Virus Type 2 from Patients Living in Southern France

et al. 2004

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“…This mutation has also been reported to affect sensitivity to some PR inhibitors (51). In the simian immunodeficiency virus SIVmac and HIV-2 PRs, position 47 is naturally occupied by valine, but in these cases the position 32 residue is isoleucine rather than the valine found in the HIV-1 PR; this may represent a compensatory mutation since in each case the ␦ carbon of the isoleucine (Ile-47 of HIV-1 and Ile-32 of SIVmac and HIV-2) is in approximately the same position (52,53).…”

Section: Discussionmentioning

confidence: 99%

Sequence requirements of the HIV-1 protease flap region determined by saturation mutagenesis and kinetic analysis of flap mutants

Shao

Everitt

Manchester

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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“…This transition-state mimic offered several advantages over other isosteres including the elimination of a chiral center by replacement of the carbon bearing P 1 0 substi- tuent and access to a broad range of substituents by simple acylation chemistry. Initial optimization studies were based on X-ray crystal data of an aza-peptide inhibitor in complex with HIV PR [108]. Variations of R 1 (see Fig.…”

Section: Drug Optimizationmentioning

confidence: 99%

TheFDAApprovedHIV‐1 Protease Inhibitors for Treatment ofHIV/AIDS

Ghosh

Anderson

Mitsuya

2010

Burger's Medicinal Chemistry and Drug Discovery

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Over the past two decades, HIV protease inhibitors have helped revolutionize the treatment of HIV/AIDS transforming this deadly ailment into a more manageable chronic infection. Due to intensive research in the area, a variety of protease inhibitors are now commercially available each of which possesses distinct characteristics and a unique tale of discovery. This manuscript reviews the design and development of the 10 currently available protease inhibitors saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, tipranavir, and darunavir. Special attention is given to the research efforts leading to their discovery and the successes and limitations of these drugs in the clinics. A brief review of the biology associated with the HIV‐1 protease target is provided in addition to a discussion of novel drug candidates currently under investigation.

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Comparative analysis of the X-ray structures of HIV-1 and HIV-2 proteases in complex with CGP 53820, a novel pseudosymmetric inhibitor

Abstract: Minor sequence changes in subsites at the active site can explain some of the observed differences in substrate and inhibitor binding between the two enzymes. The information gained from this investigation may help in the design of equipotent HIV-1/HIV-2 protease inhibitors.

Cited by 65 publications

References 40 publications

Polymorphism and Drug-Selected Mutations in the Protease Gene of Human Immunodeficiency Virus Type 2 from Patients Living in Southern France

Polymorphism and Drug-Selected Mutations in the Protease Gene of Human Immunodeficiency Virus Type 2 from Patients Living in Southern France

Sequence requirements of the HIV-1 protease flap region determined by saturation mutagenesis and kinetic analysis of flap mutants

TheFDAApprovedHIV‐1 Protease Inhibitors for Treatment ofHIV/AIDS

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