ACTIVITY OF LYTIC PEPTIDES AGAINST INTRACELLULAR TRYPANOSOMA-CRUZI AMASTIGOTES IN-VITRO AND PARASITEMIAS IN MICE

Three oecropin-like lytic peptides (DC-1, DC-2, and DC-2R) were synthe sized with virtually no sequence homology with the natural compound (c ecropin B) while retaining the charge distribution, amphipathic, and h ydrophobic properties of the natural compound. A fourth analog (alpha- Pi) without these later properties, but a similar molecular weight, wa s also synthesized as a nonlytic peptide control. The 3 lytic peptides were examined for their ability to kill Trypanosoma cruzi trypomastig otes in vitro, intracellular amastigotes in vitro, and their toxicity to a mammalian cell line. DC-2 at 5 mu M and DC-1 and DC-2R at 10 mu M were 100% effective in killing T. cruzi trypomastigotes in vitro, sug gesting at least a 10-fold increase in lytic activity over previous te sted lytic peptide analogues, SB-37 and Shiva-1. When T. cruzi-infecte d Veto cells were treated with a single or double exposure of low conc entrations (2.5 mu M) of DC-1, DC-2, and DC-2R there was a significant (P < 0.05) reduction in amastigote numbers/cell when compared to untr eated and alpha-Pi-treated T. cruzi-infected cells. Vero cells alone t reated with the lytic peptides showed no reduction in number or toxici ty. One of the peptides (DC-1) was tested for its toxicity in GT mice and its ability to reduce parasitemias in T. cruzi-infected AJ mice. N o untoward effects were seen in Al mice injected intravenously with 50 mu g/mouse daily for 10 days. There was a significant (P < 0.05) redu ction in parasitemia and mortality by day 14 postinoculation(from 100% to 0%) in T. cruzi-infected AJ mice given 25 mu g of DC-1/mouse on da ys 2, 4, 6, 8, and 10 postinoculation.