Pneumocystis carinii pneumonia (PCP)_ is the most common serious opportunistic infection in patients with acquired immunodeficiency syndrome (AIDS) and is a major cause of mortality in these patients. Patients with HIV/AIDS and a history of stimulant abuse may be particularly vulnerable to neurotoxicity leading to cognitive impairment. For instance, AIDS dementia and a abuse of psychostimulants (e.g. amphetamines and cocaine) are associated with neurotoxicity presumably caused by activation of the N-methyl-D-aspartate (NMDA) receptors systems. Pentamidine is one of the drugs of choice used extensively for the treatment of AIDS-related PCP. Recently, this drug was shown to be potent NMDA receptor antagonist with neuroprotective properties. However, the drug is associated with a high incidence of toxic side effects which limits its use. There is therefore, a critical need for more potent and less toxic anti- PCR drugs with effects which limits its use. There is therefore, a critical need for more potent and less toxic anti-PCP drugs with neuroprotective effects for treating this population of stimulant-abusing AIDS patients. Pentamidine is a flexible molecule and can assume a number of interconvertible conformations. Its molecular mechanism(s) of action is (re unclear. We hypothesize that the conformational flexibility of pentamidine allows to bind to different macromolecules and this may account at least in part, for the therapeutic as well as toxic actions of the drug. Our goal is to separate the therapeutic actions of pentamidine from its toxic actions via conformation-biological activity relationship studies. To test this hypothesis, we propose to conduct the following studies: a) design and synthesize conformational restricted analogues related to pentamidine; b) determine the physicochemical properties (pKa and log P) of the synthesized compounds; c) evaluate the in vitro anti-PCR activity of the synthesized compounds in a P. carinii cultured model; d) evaluate the in vivo anti-PCR activity and toxicity of the most promising compounds in an animal model of the disease; e) evaluate the in vitro NMDA receptor antagonist activity and neuroprotective effects of the synthesized compounds; f) study the interactions of the proposed pentamidine analogues with DNA t the molecular level via thermal denaturation and mass spectrometry techniques. The information gained will be valuable not only in determining the mechanism(s) of action of the pentamidine analogues, but may also result in the development of a more effective and safer anti-PCR agent with neuroprotective actions.
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