ARS | Publication request: THE POTENTIAL OF POLYAMINE ANALOGS AS ANTICRYPTOSPORIDIAL AGENTS

Submitted to: Society of Protozoologists International Workshop on Opportunistic Protists
Publication Type: Abstract Only
Publication Acceptance Date: July 15, 2001
Publication Date: N/A

Technical Abstract: Polyamines are cationic molecules containing 3 or more amines present at varying amounts and composition in all cells so far examined. The opportunistic parasite Cryptosporidium parvum has a polyamine biosynthetic pathway characteristic of plants and some bacteria, but atypical of nonphotosynthetic eukaryotes. We have recently found that these parasites also possess a proton driven polyamine transport mechanism with high affinity for spermine. Once internalized, spermine is rapidly retroconverted to spermidine and putrescine by the combined actions of spermine:spermidine N**1-acetyltransferase (SSAT) and polyamine oxidase (PAO). A series of bis-ethyl conformationally restricted and unrestricted analogs were synthesized and tested for ability to be transported by the parasite and block polyamine retroconversion. It was found that bis-ethyl unrestricted analogs were competitive inhibitors of SSAT with Ki values of approximately twice the apparent Km for spermine. In contrast, the restricted analogs were found to be mixed inhibitors with much lower Ki values in the order of one-half to one-third the apparent Km for spermine. The bis-ethyl restricted analogs were found to be effective in curing a T- cell receptor (TCR) alpha-deficient mouse model and indicate the utility of this class of compound as potential anticryptosporidial agents.