Pneumocystis Carinii pneumonia (PCP) is an opportunistic infection seen in many immunocompromised individuals, most notably in patients with acquired immunodeficiency syndrome (AIDS). Pentamidine is currently one of the drugs of choice in treating patients with AIDS. The drug, however, is associated with a high incidence of toxic side effects among which is hepatitis. Since alcohol consumption is a major risk factor for liver cirrhosis, alcoholic AIDS patients are at a greater risk of death from hepatotoxicity. There is, therefore, an urgent need for safer and less hepatotoxic drugs for treatment of PCP in this population of AIDS patients. At present, the molecular mechanism of action of pentamidine against Pneumocystis Carinii has not been firmly established. However, the drug is known to interact with a number of macromolecules including DNA in the pathogen. Being a flexible molecule, pentamidine can assume a number of interconvertible conformations. We hypothesize that this conformational flexibility allows pentamidine to bind to different macromolecules and this may account at least in part, for the therapeutic as well as toxic actions of the drug. It may therefore be possible to separate the therapeutic actions of pentamidine from its toxic actions via conformation-biological activity relationship studies. To test this hypothesis and achieve the goals of the project, we propose to conduct the following studies: a) design and synthesize conformationally restricted analogues related to pentamidine; b) evaluate the in vitro anti-PCP activity of the synthesized compounds in a P. carinii culture model; c) evaluate the in vivo anti-PCP activity and toxicity of the most promising compounds in an animal model of the disease; d) study the interactions of the proposed pentamidine analogues with DNA at the molecular level via thermal denaturation and molecular modeling studies. This section of the study is proposed because recent studies have indicated that the anti-PCP actions of pentamidine might be due to its interaction with the pathogenic genome. The information gained will be valuable not only in determining whether a correlation between drug- DNA interaction and anti-PCP efficacy or toxicity exist, but will also guide in the design of potentially more effective and safer anti-PCP agents.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Resource-Related Research Projects (R24)
Project #
5R24DA007970-05
Application #
5208328
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
1996
Total Cost
Indirect Cost
Mayence, Annie; Vanden Eynde, Jean Jacques; Krogstad, Fran M et al. (2004) Parallel solution-phase synthesis of conformationally restricted congeners of pentamidine and evaluation of their antiplasmodial activities. J Med Chem 47:2700-5
Mayence, Annie; Vanden Eynde, Jean Jacques; LeCour Jr, Louis et al. (2004) Piperazine-linked bisbenzamidines: a novel class of antileishmanial agents. Eur J Med Chem 39:547-53
Homayoun, P; Mandal, T; Landry, D et al. (2003) Controlled release of anti-cocaine catalytic antibody from biodegradable polymer microspheres. J Pharm Pharmacol 55:933-8
Donkor, Isaac O; Huang, Tien L; Tao, Bin et al. (2003) Trypanocidal activity of conformationally restricted pentamidine congeners. J Med Chem 46:1041-8
Zhang, Qiang; Ma, Peng; Iszard, Marcus et al. (2002) In vitro metabolism of R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo [1,2,3-de]1,4-benzoxazinyl]-(1-naphthalenyl) methanone mesylate, a cannabinoid receptor agonist. Drug Metab Dispos 30:1077-86
Brakta, Mohamed; Murthy, Devangachinta; Ellis, L'Ouverture et al. (2002) 9-[(Hydroxymethyl)phenyl]adenines: new aryladenine substrates of adenosine deaminase. Bioorg Med Chem Lett 12:1489-92
Mandal, Tarun K; Bostanian, Levon A; Graves, Richard A et al. (2002) Poly(D,L-lactide-co-glycolide) encapsulated poly(vinyl alcohol) hydrogel as a drug delivery system. Pharm Res 19:1713-9
Huang, T L; Tao, B; Quarshie, Y et al. (2001) N,N'-bis[4-(N-alkylamidino)phenyl]homopiperazines as anti-Pneumocystis carinii agents. Bioorg Med Chem Lett 11:2679-81
Mandal, T K; Bostanian, L A (2000) Effect of peptide loading and surfactant concentration on the characteristics of physically crosslinked hydrogel. Pharm Dev Technol 5:555-60
Mandal, T K (2000) Swelling-controlled release system for the vaginal delivery of miconazole. Eur J Pharm Biopharm 50:337-43

Showing the most recent 10 out of 17 publications