Three Rounds of Stability-Guided Optimization and Systematical Evaluation of Oncolytic Peptide LTX-315

Oncolytic peptides represent promising
novel candidates
for anticancer
treatments. In our efforts to develop oncolytic peptides possessing
both high protease stability and durable anticancer efficiency, three
rounds of optimization were conducted on the first-in-class oncolytic
peptide LTX-315. The robust synthetic method, in vitro and in vivo
anticancer activity, and anticancer mechanism were investigated. The
D-type peptides represented by FXY-12 possessed significantly improved
proteolytic stability and sustained anticancer efficiency. Strikingly,
the novel hybrid peptide FXY-30, containing one FXY-12 and two camptothecin
moieties, exhibited the most potent in vitro and in vivo anticancer
activities. The mechanism explorations indicated that FXY-30 exhibited
rapid membranolytic effects and induced severe DNA double-strand breaks
to trigger cell apoptosis. Collectively, this study not only established
robust strategies to improve the stability and anticancer potential
of oncolytic peptides but also provided valuable references for the
future development of D-type peptides-based hybrid anticancer chemotherapeutics.