Design, synthesis and screening of novel PCU-peptide/peptoid derived HIV protease inhibitors.
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Date
2011
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Abstract
The AIDS epidemic in Africa has reached dramatic proportions. Of the 42 million people infected with
HIV worldwide, 30 million are in Africa. Current available therapies have begun to transform this fatal
disease into a chronic condition but there are still major obstacles that have resulted in a great demand for
new and better drugs. The aim of this study was to synthesize novel and effective HIV protease
inhibitors.
This work describes the first account of pentacycloundecane (PCU)-peptide and peptoid based protease
inhibitors. These inhibitors are proposed to bind the wild type C-South African HIV protease (C-SA)
catalytic site via the norstatine or dihydroxylethelene type functional group of the PCU. The desired
compounds were synthesized by the coupling of the peptides and peptoids to the PCU cage which
resulted in a series of promising and structurally diverse HIV-1 protease inhibitors. The inhibitors were
characterized by Nuclear Magnetic Resonance (NMR) and evaluated against the wild type C-SA enzyme
for its ability to inhibit 50 % of the enzyme’s activity (IC50). Two of the compounds reported herein,
inhibited the enzyme activity at concentrations less than 80 nM.
NMR investigations indicated that the activity was related to the chirality of the PCU moiety and its
ability to induce conformations of the coupled peptide side chain. Employing the new Efficient Adiabatic
Symmetrized Rotating Overhauser Effect Spectroscopy (EASY-ROESY) technique enabled us to obtain
vital information about the 3D structure of these small linear peptides and peptoids in solution. This
technique is the first example describing the successful through space correlations of such small peptides.
Furthermore, docking and a combined quantum mechanics/molecular mechanics (QM/MM) molecular
dynamics MD simulation at the AM1 semi empirical level mirrored the observed NMR results and the
experimental IC50 activity profile of the considered inhibitors. The combination of these experimental
and theoretical methods provided a powerful insight into the interaction mode of these cage peptide and
peptoid inhibitors with the enzyme.
Description
Thesis (Ph.D.)-University of KwaZulu-Natal, Westville, 2011.
Keywords
Protease inhibitors., HIV infections--Treatment., AIDS (Disease), Theses--Pharmacy and pharmacology.