| Summary: | This study reports a series of promising and structurally diverse potential HIV-1 protease
inhibitors.
Human Immunodeficiency Virus (HIV) is the causative agent of Acquired Immune Deficiency
Syndrome (AIDS). HIV infection disrupts the immune system and makes the body susceptible to
opportunistic infections. If untreated, AIDS is generally fatal. Today, AIDS has become a long
lasting pandemic. According to the World Health Organization (WHO) and Joint United Nations
Program (UNAIDS-2009) report, it is estimated that 33.3 million men, women and children
worldwide are infected with HIV. This situation is steadily deteriorating in some parts of the
world compared to the previous years. One of the major drawbacks associated with the currently
FDA-approved anti-HIV drugs are severe side effects, toxicities, high dosage and high treatment
cost. Thus, an urgent need for new drugs to combat HIV is apparent.
In the first part of the study, research efforts were focused to synthesize potent
pentacycloundecane (PCU) derived peptide and peptoids as protease inhibitors. It is proposed
that these inhibitors bind to wild type C-South African HIV protease (C-SA) catalytic site via a
non-cleavable or non-hydrolysable cyclic ether bond for the first polycyclic cage compound and
via a dihydroxylethelene type functional group for the second cage compound. The desired
compounds were synthesized by coupling of the peptides and peptoids to the PCU derived cage.
Second part of the study involves, biological evaluation against wild type C-SA enzyme and
characterization of the synthesized compounds by Nuclear Magnetic Resonances (NMR). All
the synthesized novel compounds were evaluated against wild type C-SA enzyme for their
ability to inhibit 50% of the enzyme’s activity (IC50). Some of the compounds reported herein
showed promising activity by inhibiting the enzyme activity at concentrations of less than 0.6
nM. 2D NMR investigations employing a new Efficient Adiabatic Symmetrized Rotating
Overhauser Effect Spectroscopy (ROESY / NOESY) technique enabled the attainment of vital
information about the 3D structure of these small linear peptides and peptoids in solution. The
activity could be related to conformations induced by the PCU moiety on the coupled peptide
side chain. Further quantum mechanics/molecular mechanics/molecular dynamics
(QM/MM/MD) simulations were carried out to confirm the observed NMR experimental results.
Docking studies were performed for the synthesized compounds. Binding energies obtained
from the docking calculations were then used to further validate the experimental IC50 results.
These experimental and theoretical methods provided valuable insight into the interaction mode
of these cage peptide and peptoids inhibitors with the enzyme. === Thesis (Ph.D.)-Unversity of KwaZulu-Natal, Westville, 2012.
|
|---|
