Evaluation of topoisomers of snake venom-derived peptides as potential antimicrobial and antitumor agents

This thesis reports an investigation of the effect of topoisomeric modification on the activity of two peptides: crotalicidin (Ctn), a cathelicidin from the venom of a South American rattlesnake, and Ctn[15-34], a Ctn segment with interesting antimicrobial and antitumoral properties, as well as excellent serum stability. Topoisomeric refers to composition-identical (hence isomeric) yet three-dimensionally distinct (hence topo-) variants of a biomolecule where the structural maneuvers bring about potentially useful physiological effects. For peptides, the topoisomer term is often reserved to describe all-D-amino acid versions with sequences identical [i.e., enantio (e) form] or fully reversed [i.e., retroenantio (re)] relative to the native primary structure. To comprehensively assess the properties and activities of Ctn and Ctn[15-34] e and re topoisomers, I have compared them with both the parent peptide and its sequence-inverted variant [retro (r) form, also treated as a topoisomer]. While all topoisomers were active against gram-negative bacteria and tumor cells, those featuring D-amino acids were more cytotoxic than their L- counterparts towards normal cells. Even so, the higher stability of the e and re versions in human fluids prompted further exploration. Thus Ctn[15-34], Ctn re and Ctn[15-34] re were selected for an in vivo efficacy evaluation of their anti-infective potential in a murine model of Acinetobacter baumannii systemic infection. Following an in vivo toxicology study in CD1 mice, Ctn[15-34] re was deemed too toxic at the examined doses and excluded. For the remaining two topoisomers, Ctn[15-34] and Ctn re, a single intraperitoneal dose did not ensure mice survival. For Ctn[15-34] in particular, reasonably good results warranted further investigation despite some animals' deaths. Unfortunately, a three-day regimen of Ctn[15-34] intraperitoneal injections was lethal for all animals after the first day. Based on these results, this thesis is a sobering reminder that topoisomeric modification of ...