Harnessing a bis-electrophilic boronic acid lynchpin for azaborolo thiazolidine (ABT) grafting in cyclic peptides.
| Autor: | Das BK; Biomimetic Peptide Engineering Laboratory, Department of Chemistry, Indian Institute of Technology Ropar Rupnagar Punjab 140001 India anupamba@iitrpr.ac.in., Chowdhury A; Biomimetic Peptide Engineering Laboratory, Department of Chemistry, Indian Institute of Technology Ropar Rupnagar Punjab 140001 India anupamba@iitrpr.ac.in., Chatterjee S; Biomimetic Peptide Engineering Laboratory, Department of Chemistry, Indian Institute of Technology Ropar Rupnagar Punjab 140001 India anupamba@iitrpr.ac.in., Tripathi NM; Biomimetic Peptide Engineering Laboratory, Department of Chemistry, Indian Institute of Technology Ropar Rupnagar Punjab 140001 India anupamba@iitrpr.ac.in., Pati B; Biomimetic Peptide Engineering Laboratory, Department of Chemistry, Indian Institute of Technology Ropar Rupnagar Punjab 140001 India anupamba@iitrpr.ac.in., Dutta S; Biomimetic Peptide Engineering Laboratory, Department of Chemistry, Indian Institute of Technology Ropar Rupnagar Punjab 140001 India anupamba@iitrpr.ac.in., Bandyopadhyay A; Biomimetic Peptide Engineering Laboratory, Department of Chemistry, Indian Institute of Technology Ropar Rupnagar Punjab 140001 India anupamba@iitrpr.ac.in. |
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| Jazyk: | angličtina |
| Zdroj: | Chemical science [Chem Sci] 2024 Jul 30. Date of Electronic Publication: 2024 Jul 30. |
| DOI: | 10.1039/d4sc04348k |
| Abstrakt: | Chemical modifications of native peptides have significantly advanced modern drug discovery in recent decades. On this front, the installation of multitasking molecular grafts onto macrocyclic peptides offers numerous opportunities in biomedical applications. Here, we showcase a new class of borono-cyclic peptides featuring an azaborolo thiazolidine (ABT) graft, which can be readily assembled utilizing a bis-electrophilic boronic acid lynchpin while harnessing the inherent reactivity difference (>10 3 M -1 s -1 ) between the N-terminal cysteine and backbone cysteine for rapid and highly regioselective macrocyclization (∼1 h) under physiological conditions. The ABT-crosslinked peptides are fairly stable in endogenous environments, but can provide the linear diazaborine peptides via treatment with α-nucleophiles. This efficient peptide crosslinking protocol was further extended for regioselective bicyclizations and engineering of α-helical structures. Finally, ABT-grafted peptides were exploited in biorthogonal conjugation, leading to highly effective intracellular delivery of an apoptotic peptide (KLA) in cancer cells. The mechanism of action by which ABT-grafted KLA peptide induces apoptosis was also explored. Competing Interests: There are no conflicts to declare. (This journal is © The Royal Society of Chemistry.) |
| Databáze: | MEDLINE |
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