Thiocarbazate building blocks enable the construction of azapeptides for rapid development of therapeutic candidates

Ahmad Altiti (), Mingzhu He, Sonya VanPatten, Kai Fan 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 K. Hudson, Stavros Zanos, Myoungsun Son, Barbara Sherry, Thomas R. Coleman and Yousef Al-Abed ()
Additional contact information
Ahmad Altiti: Feinstein Institutes for Medical Research, Northwell Health
Mingzhu He: Feinstein Institutes for Medical Research, Northwell Health
Sonya VanPatten: Feinstein Institutes for Medical Research, Northwell Health
Kai Fan Cheng: Feinstein Institutes for Medical Research, Northwell Health
Umair Ahmed: Feinstein Institutes for Medical Research, Northwell Health
Pui Yan Chiu: Feinstein Institutes for Medical Research
Ibrahim T. Mughrabi: Feinstein Institutes for Medical Research, Northwell Health
Bayan Al Jabari: Feinstein Institutes for Medical Research, Northwell Health
Ronald M. Burch: Applied Immunotherapeutics, Inc
Kirk R. Manogue: Feinstein Institutes for Medical Research
Kevin J. Tracey: Feinstein Institutes for Medical Research, Northwell Health
Betty Diamond: Feinstein Institutes for Medical Research
Christine N. Metz: Feinstein Institutes for Medical Research
Huan Yang: Feinstein Institutes for Medical Research, Northwell Health
LaQueta K. Hudson: Donald and Barbara Zucker School of Medicine at Hofstra/Northwell
Stavros Zanos: Feinstein Institutes for Medical Research, Northwell Health
Myoungsun Son: Feinstein Institutes for Medical Research
Barbara Sherry: Feinstein Institutes for Medical Research
Thomas R. Coleman: Feinstein Institutes for Medical Research
Yousef Al-Abed: Feinstein Institutes for Medical Research, Northwell Health

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-34712-9

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