Presentation Title

SuFEx based click chemistry for peptide stapling

Faculty Mentor

Valery Fokin

Start Date

18-11-2017 2:15 PM

End Date

18-11-2017 3:15 PM

Location

BSC-Ursa Minor 25

Session

Poster 3

Type of Presentation

Poster

Subject Area

physical_mathematical_sciences

Abstract

Click chemistry describes the modular coupling of functional building blocks in high-yielding reactions that are broad-scope, environmentally-friendly, and insensitive to water and oxygen. The sulfur (VI) fluoride exchange (SuFEx) has been identified as a new addition to the click family due to the unique stability of the SO2F moiety, which confers inertness against acid-base reactions, resistance to oxidation and reduction, and chemoselective yields of sulfonylation products. With the recent discovery that ethenesulfonyl fluoride (ESF) is a powerful Michael acceptor for installing the SO2F group, there is potential for SuFEx chemistry to become a powerful tool in peptide stapling, a technique that locks peptide therapeutics’ conformation to improve their pharmacological effects. We envision a scenario wherein (1) a nucleophilic site (i.e. hydroxy, thiol or amino group) on the peptide undergoes conjugate addition to ESF, followed by (2) fluoride exchange with a different nucleophilic site (i.e. a tyrosine phenol) on the peptide, thus locking its conformation. Such selective modification poses potential in informing the development of chemical probes that will improve the efficacy of pharmacological delivery and drug discovery. Furthermore, the effects of various fluoride sources will be investigated to promote activation of ESF for SuFEx and Michael addition reactions. Through preliminary studies of the reactivity of ESF with simple amino acids (cysteine) and peptides (glutathione), we have observed both conjugate addition and fluoride exchange products by LC-MS and NMR. Further analysis will be pursued to understand reaction selectivity and to optimize reaction conditions.

Summary of research results to be presented

Research results will include the synthesis pathways attempted thus far to achieve desired product and note which pathways provided the most promising strategies.

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Nov 18th, 2:15 PM Nov 18th, 3:15 PM

SuFEx based click chemistry for peptide stapling

BSC-Ursa Minor 25

Click chemistry describes the modular coupling of functional building blocks in high-yielding reactions that are broad-scope, environmentally-friendly, and insensitive to water and oxygen. The sulfur (VI) fluoride exchange (SuFEx) has been identified as a new addition to the click family due to the unique stability of the SO2F moiety, which confers inertness against acid-base reactions, resistance to oxidation and reduction, and chemoselective yields of sulfonylation products. With the recent discovery that ethenesulfonyl fluoride (ESF) is a powerful Michael acceptor for installing the SO2F group, there is potential for SuFEx chemistry to become a powerful tool in peptide stapling, a technique that locks peptide therapeutics’ conformation to improve their pharmacological effects. We envision a scenario wherein (1) a nucleophilic site (i.e. hydroxy, thiol or amino group) on the peptide undergoes conjugate addition to ESF, followed by (2) fluoride exchange with a different nucleophilic site (i.e. a tyrosine phenol) on the peptide, thus locking its conformation. Such selective modification poses potential in informing the development of chemical probes that will improve the efficacy of pharmacological delivery and drug discovery. Furthermore, the effects of various fluoride sources will be investigated to promote activation of ESF for SuFEx and Michael addition reactions. Through preliminary studies of the reactivity of ESF with simple amino acids (cysteine) and peptides (glutathione), we have observed both conjugate addition and fluoride exchange products by LC-MS and NMR. Further analysis will be pursued to understand reaction selectivity and to optimize reaction conditions.