Thiocarbazate building blocks enable the construction of azapeptides for rapid development of therapeutic candidates
Ahmad S. Altiti, Mingzhu He, Sonya VanPatten, Kai Cheng, Umair Ahmed, Pui Yan Chiu, Ibrahim T. Mughrabi, Bayan Al Jabari, Ronald M. Burch, Kirk R. Manogue, Kevin J. Tracey, Betty Diamond, Christine N. Metz, Huan Yang, LaQueta Hudson, Stavros Zanos, Myoungsun Son, Barbara Sherry, Thomas R. Coleman, Yousef Al‐Abed
Abstract
Peptides, polymers of amino acids, comprise a vital and expanding therapeutic approach. Their rapid degradation by proteases, however, represents a major limitation to their therapeutic utility and chemical modifications to native peptides have been employed to mitigate this weakness. Herein, we describe functionalized thiocarbazate scaffolds as precursors of aza-amino acids, that, upon activation, can be integrated in a peptide sequence to generate azapeptides using conventional peptide synthetic methods. This methodology facilitates peptide editing-replacing targeted amino acid(s) with aza-amino acid(s) within a peptide-to form azapeptides with preferred therapeutic characteristics (extending half-life/bioavailability, while at the same time typically preserving structural features and biological activities). We demonstrate the convenience of this azapeptide synthesis platform in two well-studied peptides with short half-lives: FSSE/P5779, a tetrapeptide inhibitor of HMGB1/MD-2/TLR4 complex formation, and bradykinin, a nine-residue vasoactive peptide. This bench-stable thiocarbazate platform offers a robust and universal approach to optimize peptide-based therapeutics.