Chemotherapy for diseases caused by hemoflagellate protozoa is hampered by the toxicity of most agents in current use and by the widespread occurrence of drug resistance. The search for novel, nontoxic agents based on biochemical lesions in these parasites is an important priority which has been neglected because of economic considerations. The basis of this proposal is the rational development of a newly discovered class of compounds with in vitro and in vivo trypanocidal activity. These compounds are analogs of 5'-deoxy-5'-(methylthio)adenosine (MTA), a byproduct of polyamine biosynthesis. The most effective of these compounds, 5'-deoxy-5'-(hydroxyethylthio)adenosine (HETA) is preferentially cleaved by trypanosome but not mammalian MTA phosphorylase into adenine + a ribose-l-phosphate analog which is believed to interfere with methionine metabolism in the parasite. HETA will serve as the lead compound for the design and synthesis of a series of HETA analogs with potentially enhanced trypanocidal activity. These proposed HETA analogs will be evaluated for their in vitro and in vivo efficacy against model infections of Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense, with special attention to the identification of analogs with activity against drug resistant clinical isolates and central nervous system infections induced by trypanosomes. Analogs will also be screened for their in vitro effects against the related pathogens, Trypanosoma cruzi and Leishmania donovani. The biochemical mechanisms responsible for the selective trypanocidal activity of HETA and related analogs will also be investigated. Strategies to optimize the drug delivery characteristics of HETA and related analogs will include the synthesis of prodrug forms designed to release HETA slowly within the biological milieu. Overall, these studies are directed towards the selection of those HETA analogs with the most promising spectrum of trypanocidal and antileishmanial effects for further pharmacological development as antiparasitic agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI032975-02
Application #
3148071
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Project Start
1992-07-01
Project End
1996-04-30
Budget Start
1993-05-01
Budget End
1994-04-30
Support Year
2
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Roswell Park Cancer Institute Corp
Department
Type
DUNS #
City
Buffalo
State
NY
Country
United States
Zip Code
14263
Sufrin, Janice R; Spiess, Arthur J; Marasco Jr, Canio J et al. (2008) Novel trypanocidal analogs of 5'-(methylthio)-adenosine. Antimicrob Agents Chemother 52:211-9
Marasco Jr, Canio J; Pera, Paula J; Spiess, Arthur J et al. (2005) Improved synthesis of beta-D-6-methylpurine riboside and antitumor effects of the beta-D- and alpha-D-anomers. Molecules 10:1015-20
Goldberg, B; Rattendi, D; Lloyd, D et al. (2001) In situ kinetic characterization of methylthioadenosine transport by the adenosine transporter (P2) of the African Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense. Biochem Pharmacol 61:449-57
Bacchi, C J; Goldberg, B; Rattendi, D et al. (1999) Metabolic effects of a methylthioadenosine phosphorylase substrate analog on African trypanosomes. Biochem Pharmacol 57:89-96
Goldberg, B; Rattendi, D; Lloyd, D et al. (1998) Effects of intermediates of methionine metabolism and nucleoside analogs on S-adenosylmethionine transport by Trypanosoma brucei brucei and a drug-resistant Trypanosoma brucei rhodesiense. Biochem Pharmacol 56:95-103
Bacchi, C J; Sanabria, K; Spiess, A J et al. (1997) In vivo efficacies of 5'-methylthioadenosine analogs as trypanocides. Antimicrob Agents Chemother 41:2108-12
Sufrin, J R; Meshnick, S R; Spiess, A J et al. (1995) Methionine recycling pathways and antimalarial drug design. Antimicrob Agents Chemother 39:2511-5