A general peptide reversible macrocyclization strategy is developed based on a facile and chemoselective methionine bis-alkylation/dealkylation process.
We
report a facile thiol-yne type reaction triggered by the sulfonium
center. After facile propargylation of thiolethers, the resulting
sulfonium could undergo facile addition with thiols in aqueous media
at ambient temperature. Further applying this reaction in unprotected
peptides bearing neighboring methionine and cysteine could enable
a facile intramolecular addition to construct cyclic peptides with
better stability, good glutathione resistance, and increased cellular
uptakes. Also, the propargylated sulfonium may be used as robust and
versatile probes to target cysteines containing biomolecules.
FDA-approved HDAC inhibitors exhibit dose-limiting adverse effects; thus, we sought to improve the therapeutic windows for this class of drugs. In this report, we describe a new class of peptide-based HDAC inhibitors derived from the HDAC1-specific substrate H3K56 with improved nonspecific toxicity compared with traditional small-molecular inhibitors. We showed that our designed peptides exerted superior antiproliferation effects on cancer stem–like cells with minimal toxicity to normal cells compared with the small-molecular inhibitor SAHA, which showed nonspecific toxicity to normal and cancer cells. These peptide inhibitors also inactivated cellular HDAC1 and HDAC6 and disrupted the formation of the HDAC1, LSD1, and CoREST complex. In ovarian teratocarcinoma (PA-1) and testicular embryonic carcinoma (NTERA-2) cell xenograft animal models (5 mice/group, 50 mg/kg, every other day, intraperitoneal injection), these peptides inhibited tumor growth by 80% to 90% with negligible organ (heart, liver, spleen, lung, kidney, brain) lesions. These results represent the first attempt to design chemically stabilized peptide inhibitors to investigate HDAC inhibition in cancer stem–like cells. These novel peptide inhibitors have significantly enhanced therapeutic window and offer promising opportunities for cancer therapy.
Significance:
Selective antiproliferative effects of stabilized peptide HDAC inhibitors toward cancer stem–like cells provide a therapeutic alternative that avoids high nonspecific toxicity of current drugs.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.