HIV; Protease; inhibitor; mutant; thermodynamics; HIV Protease Inhibitors; HIV Protease; p16 protease, Human immunodeficiency virus 1; HIV Protease/drug effects; HIV Protease/genetics; HIV Protease/metabolism; HIV Protease Inhibitors/chemistry; HIV Protease Inhibitors/pharmacology; HIV-1/enzymology; Inhibitory Concentration 50; Kinetics; Molecular Docking Simulation; Mutation; Thermodynamics; HIV-1; Pharmacology; Drug Discovery
Abstract :
[en] Herein, we report the effect of nine FDA approved protease inhibitor drugs against a new HIV-1 subtype C mutant protease, E35D↑G↑S. The mutant has five mutations, E35D, two insertions, position 36 (G and S), and D60E. Kinetics, inhibition constants, vitality, Gibbs free binding energies are reported. The variant showed a decreased affinity for substrate and low catalytic efficiency compared to the wild type. There was a significant decrease in the binding of seven FDA approved protease inhibitors against the mutant (p < .0001). Amprenavir and ritonavir showed the least decrease, but still significant reduced activity in comparison to the wildtype (4 and 5 folds, respectively, p = .0021 and .003, respectively). Nelfinavir and atazanavir were the worst inhibitors against the variant as seen from the IC50, with values of 1401 ± 3.0 and 685 ± 3.0 nM, respectively. Thermodynamics data showed less favourable Gibbs free binding energies for the protease inhibitors to the mutant.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Maseko, Sibusiso Bonginkhost ; a Catalysis and Peptide Research Unit, School of Health Sciences, University of KwaZulu-Natal , Durban , South Africa
Padayachee, Eden; a Catalysis and Peptide Research Unit, School of Health Sciences, University of KwaZulu-Natal , Durban , South Africa
Maphumulo, Siyabonga; a Catalysis and Peptide Research Unit, School of Health Sciences, University of KwaZulu-Natal , Durban , South Africa
Govender, Thavendran; a Catalysis and Peptide Research Unit, School of Health Sciences, University of KwaZulu-Natal , Durban , South Africa
Sayed, Yasien; b Protein Structure-Function Research Unit, School of Molecular and Cell Biology, University of the Witwatersrand , Wits , South Africa
Maguire, Glenn; a Catalysis and Peptide Research Unit, School of Health Sciences, University of KwaZulu-Natal , Durban , South Africa ; c School of Chemistry and Physics, University of KwaZulu-Natal , Durban , South Africa
Lin, Johnson; d School of Life Sciences, University of KwaZulu-Natal , Durban , South Africa
Naicker, Tricia; a Catalysis and Peptide Research Unit, School of Health Sciences, University of KwaZulu-Natal , Durban , South Africa
Baijnath, Sooraj; a Catalysis and Peptide Research Unit, School of Health Sciences, University of KwaZulu-Natal , Durban , South Africa
Gerhardus, Kruger Hendrik ; a Catalysis and Peptide Research Unit, School of Health Sciences, University of KwaZulu-Natal , Durban , South Africa
Language :
English
Title :
Kinetic and thermodynamic characterisation of HIV-protease inhibitors against E35D↑G↑S mutant in the South African HIV-1 subtype C protease.
Publication date :
December 2019
Journal title :
Journal of Enzyme Inhibition and Medicinal Chemistry
The authors thank the NRF, UKZN, University of the Witwatersrand, Aspen Pharmacare, and MRC (SA) for financial support. The protease sequence was supplied by Professor Lynn Morris (Head: HIV Research, National Institute for Communicable Diseases, South Africa).The authors thank the NRF, UKZN, University of the Witwatersrand, Aspen Pharmacare, and MRC (SA) for financial support. The protease sequence was supplied by Professor Lynn Morris (Head: HIV Research, National Institute for Communicable Diseases, South Africa).
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