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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
Synthesis, 2D-NMR and molecular modelling studies of pentacycloundecane lactam-peptides and peptoids as potential HIV-1 wild type C-SA protease inhibitors
Journal of Enzyme Inhibition and Medicinal Chemistry, Volume 28, No. 1, Year 2013
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Description
In this study, eight non-natural peptides and peptoids incorporating the pentacycloundecane (PCU) lactam were designed and synthesized as potential inhibitors of the wild type C-SA HIV-protease. Five of these inhibitors gave IC50 values ranging from 0.5 up to 0.75 μM against the resistance-prone wild type C-South African HIV-protease. NMR EASY-ROESY studies enabled us to describe the secondary structure of three of these compounds in solution. The 3D structures of the selected cage peptides were also modelled in solution using QM/MM/MD simulations. Satisfactory agreement between the NMR observations and the low energy calculated structures exists. Only one of these inhibitors (11 peptoid), which showed the best IC50(0.5 μM), exhibited a definable 3-D structure in solution. Autodock4 and AutodockVina were used to model the potential interaction between these inhibitors and the HIV-PR. It appears that the docking results are too crude to be correlated with the relative narrow range of experimental IC50 values (0.5-10 μM). The PCU-peptides and peptoides were several orders less toxic (145 μM for 11 and 102 μM for 11 peptoid) to human MT-4 cells than lopinavir (0.025 μM). This is the first example of a polycyclic cage framework to be employed as an HIV-PR transition state analogue inhibitor and can potentially be utilized for other diseases related proteases. Graphical abstract: PCU-diastereomers peptide and peptoid inhibitors with arrows showing the observed EASY-ROESY correlations. © 2013 Informa UK, Ltd.
Authors & Co-Authors
Makatini, Maya Mellisa
South Africa, Durban
School of Pharmacy and Pharmacology
Petzold, Katja
South Africa, Durban
University of Kwazulu-natal
Nahum Alves, Cl?udio Nahum
Brazil, Belem
Universidade Federal do Pará
Arvidsson, Per I.
South Africa, Durban
School of Pharmacy and Pharmacology
Sweden, Uppsala
Biomedicinskt Centrum
Sweden, Sodertalje
Astrazeneca r and D Södertälje
Honarparvar, Bahareh
South Africa, Durban
University of Kwazulu-natal
Govender, Patrick
South Africa, Durban
University of Kwazulu-natal
Govender, Thavendran
South Africa, Durban
School of Pharmacy and Pharmacology
Kruger, Hendrik G.
South Africa, Durban
University of Kwazulu-natal
Sayed, Yasien
South Africa, Johannesburg
University of the Witwatersrand
Jerônimolameira,
Brazil, Belem
Universidade Federal do Pará
Maguire, Glenn E.M.
South Africa, Durban
University of Kwazulu-natal
Soliman, Mahmoud E.S.
South Africa, Durban
School of Pharmacy and Pharmacology
Egypt, Zagazig
Faculty of Pharmacy
Statistics
Citations: 23
Authors: 12
Affiliations: 7
Identifiers
Doi:
10.3109/14756366.2011.633907
ISSN:
14756366
e-ISSN:
14756374
Research Areas
Environmental
Infectious Diseases