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Design, synthesis and evaluation of a potent substrate analog inhibitor identified by scanning Ala/Phe mutagenesis, mimicking substrate co-evolution, against multidrug-resistant HIV-1 protease.

Publication ,  Journal Article
Yedidi, RS; Muhuhi, JM; Liu, Z; Bencze, KZ; Koupparis, K; O'Connor, CE; Kovari, IA; Spaller, MR; Kovari, LC
Published in: Biochemical and biophysical research communications
September 2013

Multidrug-resistant (MDR) clinical isolate-769, human immunodeficiency virus type-1 (HIV-1) protease (PDB ID: 1TW7), was shown to exhibit wide-open flaps and an expanded active site cavity, causing loss of contacts with protease inhibitors. In the current study, the expanded active site cavity of MDR769 HIV-1 protease was screened with a series of peptide-inhibitors that were designed to mimic the natural substrate cleavage site, capsid/p2. Scanning Ala/Phe chemical mutagenesis approach was incorporated into the design of the peptide series to mimic the substrate co-evolution. Among the peptides synthesized and evaluated, a lead peptide (6a) with potent activity (IC50: 4.4nM) was identified against the MDR769 HIV-1 protease. Isothermal titration calorimetry data showed favorable binding profile for 6a against both wild type and MDR769 HIV-1 protease variants. Nuclear magnetic resonance spectrum of (15)N-labeled MDR769 HIV-1 protease in complex with 6a showed some major perturbations in chemical shift, supporting the peptide induced conformational changes in protease. Modeling analysis revealed multiple contacts between 6a and MDR769 HIV-1 protease. The lead peptide-inhibitor, 6a, with high potency and good binding profile can be used as the basis for developing potent small molecule inhibitors against MDR variants of HIV.

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Published In

Biochemical and biophysical research communications

DOI

EISSN

1090-2104

ISSN

0006-291X

Publication Date

September 2013

Volume

438

Issue

4

Start / End Page

703 / 708

Related Subject Headings

  • Peptides
  • Peptide Library
  • Mutagenesis
  • Molecular Docking Simulation
  • Humans
  • HIV-1
  • HIV Protease Inhibitors
  • HIV Protease
  • HIV Infections
  • Drug Resistance, Multiple, Viral
 

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Yedidi, R. S., Muhuhi, J. M., Liu, Z., Bencze, K. Z., Koupparis, K., O’Connor, C. E., … Kovari, L. C. (2013). Design, synthesis and evaluation of a potent substrate analog inhibitor identified by scanning Ala/Phe mutagenesis, mimicking substrate co-evolution, against multidrug-resistant HIV-1 protease. Biochemical and Biophysical Research Communications, 438(4), 703–708. https://doi.org/10.1016/j.bbrc.2013.07.117
Yedidi, Ravikiran S., Joseck M. Muhuhi, Zhigang Liu, Krisztina Z. Bencze, Kyriacos Koupparis, Carrie E. O’Connor, Iulia A. Kovari, Mark R. Spaller, and Ladislau C. Kovari. “Design, synthesis and evaluation of a potent substrate analog inhibitor identified by scanning Ala/Phe mutagenesis, mimicking substrate co-evolution, against multidrug-resistant HIV-1 protease.Biochemical and Biophysical Research Communications 438, no. 4 (September 2013): 703–8. https://doi.org/10.1016/j.bbrc.2013.07.117.
Yedidi RS, Muhuhi JM, Liu Z, Bencze KZ, Koupparis K, O’Connor CE, et al. Design, synthesis and evaluation of a potent substrate analog inhibitor identified by scanning Ala/Phe mutagenesis, mimicking substrate co-evolution, against multidrug-resistant HIV-1 protease. Biochemical and biophysical research communications. 2013 Sep;438(4):703–8.
Yedidi, Ravikiran S., et al. “Design, synthesis and evaluation of a potent substrate analog inhibitor identified by scanning Ala/Phe mutagenesis, mimicking substrate co-evolution, against multidrug-resistant HIV-1 protease.Biochemical and Biophysical Research Communications, vol. 438, no. 4, Sept. 2013, pp. 703–08. Epmc, doi:10.1016/j.bbrc.2013.07.117.
Yedidi RS, Muhuhi JM, Liu Z, Bencze KZ, Koupparis K, O’Connor CE, Kovari IA, Spaller MR, Kovari LC. Design, synthesis and evaluation of a potent substrate analog inhibitor identified by scanning Ala/Phe mutagenesis, mimicking substrate co-evolution, against multidrug-resistant HIV-1 protease. Biochemical and biophysical research communications. 2013 Sep;438(4):703–708.
Journal cover image

Published In

Biochemical and biophysical research communications

DOI

EISSN

1090-2104

ISSN

0006-291X

Publication Date

September 2013

Volume

438

Issue

4

Start / End Page

703 / 708

Related Subject Headings

  • Peptides
  • Peptide Library
  • Mutagenesis
  • Molecular Docking Simulation
  • Humans
  • HIV-1
  • HIV Protease Inhibitors
  • HIV Protease
  • HIV Infections
  • Drug Resistance, Multiple, Viral