分会

第三十七分会：生物大分子与生命过程

摘要

Cytotoxic peptides have been considered as promising candidates for anticancer treatments. One of the most promising anticancer peptides is the LTX-315 (OncoporeTM), which has been in phase I/II clinical trials. Nevertheless, the problems represented by the poor proteolytic stability should be addressed to facilitate further clinical applications of LTX-315. Therefore, in this study, twenty-one LTX-315 based derivatives and hybrid peptides were rationally designed, efficiently synthesized, systematically evaluated both in vitro and in vivo. Strikingly, the proteolytic stability, anticancer aging and internally quenched fluorescent (IQF) substrates experiments jointly demonstrated that D-type anticancer peptides, represented by FXY-2, possessed both the most sustained anticancer efficiency and highest proteolytic stability. In order to further enhance the anticancer efficiency of D-type FXY-2, the hybrid peptides by covalent conjugation of FXY-2 with different amounts of camptothecin were designed and systematically evaluated. Compared with the parent LTX-315, the conjugate camptothecin-FXY-2, named FXY-20, exhibited about ten-fold increase for the in vitro cytotoxicity against a panel of cancer cell lines and superior in vivo anticancer efficiency in the mouse cancer model. Especially, FXY-20 could disrupt the integrity of cancer cell membrane, target mitochondria and reduce the mitochondrial membrane potential, the combinations of which induce the rapid cell death. Our study may provide valuable references for the development of D-type oncolytic peptides.

关键词

D-type oncolytic peptide;camptothecin;LTX-315;Hybrid peptide;Solid Phase Peptide Synthesis

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