N,N'-thiophene-substituted polyamine analogs inhibit mammalian host cell invasion and intracellular multiplication of Trypanosoma cruzi.
We studied the effects of two N,N'-thiophene-substituted polyamine analogs (MDL 28302 and MDL 29431) on the capacities of Trypanosoma cruzi, the etiologic agent of Chagas' disease, to invade and multiply within a mammalian host cell. Both compounds inhibited infectivity significantly in a time- and concentration-dependent manner. This inhibition resulted from a selective effect on the parasite, because pretreatment of T. cruzi but not host cell cultures with either MDL 28302 or MDL 29431 reduced infectivity. The parasite gradually recovered its infective capacity after removal of unincorporated polyamine analog, denoting the reversible nature of the inhibitory effect. Some biochemical modification of MDL 28302 and MDL 29431 appeared to be required for their inhibitory activities to be exerted, since the effects of these drugs on T. cruzi infectivity were abrogated by MDL 72527, a drug known to inhibit polyamine oxidase (PAO) activity specifically. Supporting the notion of that products of MDL 28302 and MDL 29431 oxidation by PAO were involved in the activity of these compounds was the finding that PAO competitive substrates (N1-acetylspermine and N1-acetylspermidine) also abolished the inhibition of T. cruzi infectivity mediated by MDL 28302 or MDL 29431. However, we can not rule out that MDL 72527 and the PAO competitive substrates might have altered an alternative mechanism because no significant polyamine oxidase activity could be demonstrated in preparations of lysed or intact T. cruzi in assays monitoring conversion of [14C]spermine to [14C]spermidine. When either MDL 28302 or MDL 29431 was added to infected cell cultures, a marked reduction in the rate of intracellular parasite growth ensued.(ABSTRACT TRUNCATED AT 250 WORDS)
Majumder
S
S
Department of Microbiology, Michigan State University, East Lansing 48824.
Kierszenbaum
F
F
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D014355:Chagas Disease / Q000188:drug therapy; D006321:Heart / Q000469:parasitology; D006790:Host-Parasite Interactions / Q000187:drug effects; D007700:Kinetics; D051379:Mice; D008813:Mice, Inbred ICR; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000037:antagonists & inhibitors / Q000378:metabolism; D011073:Polyamines / Q000494:pharmacology*; D011700:Putrescine / Q000031:analogs & derivatives / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000166:cytology / Q000187:drug effects* / Q000472:pathogenicity; D014774:Virulence / Q000187:drug effects; D000097667:Polyamine Oxidase
D000587:Oxidoreductases Acting on CH-NH Group Donors; D011073:Polyamines; D011700:Putrescine; D013876:Thiophenes; D000097667:Polyamine Oxidase; C083871:MDL 28302; C083870:MDL 29431; C044445:MDL 72527