Rationally Designed Amanitins Achieve Enhanced Cytotoxicity

Abstract

For 70 years, α-amanitin, the most cytotoxic peptide in its class, has been without a synthetic rival; through synthesis, we address the structure–activity relationships to inform the design of new amatoxins and disclose analogues that are more cytotoxic than the natural product when evaluated on CHO, HEK293, and HeLa cells, whereas on liver-derived HepG2 cells, the same toxins show diminished cytotoxicity.

Bicyclic peptides: Paving the road for therapeutics of the future

“…[28] While α-amanitin is already one of the deadliest toxins known, [28] the group has recently derived multiple bicyclic peptides with enhanced cytotoxicity using rational drug design. [35] SFTI-1 is a head-to-tail cyclic peptide with a disulfide bridge that inhibits the serine protease trypsin with a sub-nanomolar inhibition constant (Figure 3b). [29] It has been the subject of extensive research including as a platform for protease inhibitors or as a molecular grafting scaffold.…”

“…(a) α-Amanitin. [35] (b) SFTI-1. [36] (c) Theonellamide K. [31] (d) Nyuzenamide C. [33] S C H E M E 1 Bicyclization of peptides with three cysteines using TBMB.…”

“…[ 28 ] While α‐amanitin is already one of the deadliest toxins known, [ 28 ] the group has recently derived multiple bicyclic peptides with enhanced cytotoxicity using rational drug design. [ 35 ]…”