{"id":{"repo_id":"milano","oai_identifier":"oai:air.unimi.it:2434/1205020"},"canonical_url":"https://search.dev.ndltd.org/etd/milano/oai:air.unimi.it:2434/1205020","repository":{"repo_id":"milano","name":"Università degli Studi di Milano","base_url":"https://air.unimi.it/oai/request"},"display":{"title":"SALICYLALDEHYDE-TAGGED PEPTIDES FOR THE REVERSIBLE-COVALENT ENGAGEMENT OF PROTEIN LYSINE RESIDUES","abstract":"Covalent drug discovery has recently re-emerged as a powerful approach for targeting clinically-relevant proteins, offering enhanced potency and selectivity through controlled covalent interactions. In particular, reversible covalent (RC) chemistry combines the strength of covalent binding with the tunability of non-covalent interactions, mitigating the risks of permanent off-target reactivity. Within this context, this PhD thesis explores the use of salicylaldehyde (SA) as a reversible electrophilic warhead for peptide-based ligand design. The first part of this thesis focuses on the synthesis of SA-modified amino acids and their incorporation into model peptides. Later on, a more straightforward and versatile approach was devised, consisting in the late-stage peptide functionalization with copper-catalyzed azide- alkyne cycloaddition (CuAAC). This second strategy enabled efficient installation of SA moieties onto pre-assembled peptides specific for two protein targets, namely SHP2 and NEMO. Moreover, using human serum albumin as model target, the CuAAC protocol was instrumental for the design of a new combinatorial approach to SA-tagged small molecules. The final part of the work, carried out at the University of Tokyo, integrates SA-based reversible covalent chemistry into the RaPID (Random nonstandard Peptides Integrated Discovery) platform, paving the way to a novel strategy towards macrocyclic peptide libraries displaying a Lys-engaging electrophile. Overall, this work expands the chemical space of peptide-based RC ligands, providing new synthetic and methodological tools to access selective, tunable covalent binders to target specific proteins or to inhibit clinically-relevant protein-protein interactions.","abstract_html":"Covalent drug discovery has recently re-emerged as a powerful approach for targeting clinically-relevant proteins, offering enhanced potency and selectivity through controlled covalent interactions. In particular, reversible covalent (RC) chemistry combines the strength of covalent binding with the tunability of non-covalent interactions, mitigating the risks of permanent off-target reactivity. Within this context, this PhD thesis explores the use of salicylaldehyde (SA) as a reversible electrophilic warhead for peptide-based ligand design. The first part of this thesis focuses on the synthesis of SA-modified amino acids and their incorporation into model peptides. Later on, a more straightforward and versatile approach was devised, consisting in the late-stage peptide functionalization with copper-catalyzed azide- alkyne cycloaddition (CuAAC). This second strategy enabled efficient installation of SA moieties onto pre-assembled peptides specific for two protein targets, namely SHP2 and NEMO. Moreover, using human serum albumin as model target, the CuAAC protocol was instrumental for the design of a new combinatorial approach to SA-tagged small molecules. The final part of the work, carried out at the University of Tokyo, integrates SA-based reversible covalent chemistry into the RaPID (Random nonstandard Peptides Integrated Discovery) platform, paving the way to a novel strategy towards macrocyclic peptide libraries displaying a Lys-engaging electrophile. Overall, this work expands the chemical space of peptide-based RC ligands, providing new synthetic and methodological tools to access selective, tunable covalent binders to target specific proteins or to inhibit clinically-relevant protein-protein interactions.","abstract_has_math":false,"creators":["MASON, MATTIA"],"institution":"Università degli Studi di Milano","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["tutor: A. Dal Corso ; PhD coordinator: D. Passarella","M. Mason","DAL CORSO, ALBERTO","PASSARELLA, DANIELE"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2026,"date_issued":"2026-01-16","date_published":"2026-01-16","updated_at":"2026-07-27T20:19:05Z","subjects":["Settore CHEM-05/A - Chimica organica"],"languages":["eng"],"rights":["info:eu-repo/semantics/embargoedAccess","license:Creative commons","license uri:http://creativecommons.org/licenses/by-sa/4.0/"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/2434/1205020","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["tutor: A. Dal Corso ; PhD coordinator: D. Passarella","M. 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In particular, reversible covalent (RC) chemistry combines the strength of covalent binding with the tunability of non-covalent interactions, mitigating the risks of permanent off-target reactivity. Within this context, this PhD thesis explores the use of salicylaldehyde (SA) as a reversible electrophilic warhead for peptide-based ligand design. The first part of this thesis focuses on the synthesis of SA-modified amino acids and their incorporation into model peptides. Later on, a more straightforward and versatile approach was devised, consisting in the late-stage peptide functionalization with copper-catalyzed azide- alkyne cycloaddition (CuAAC). This second strategy enabled efficient installation of SA moieties onto pre-assembled peptides specific for two protein targets, namely SHP2 and NEMO. Moreover, using human serum albumin as model target, the CuAAC protocol was instrumental for the design of a new combinatorial approach to SA-tagged small molecules. The final part of the work, carried out at the University of Tokyo, integrates SA-based reversible covalent chemistry into the RaPID (Random nonstandard Peptides Integrated Discovery) platform, paving the way to a novel strategy towards macrocyclic peptide libraries displaying a Lys-engaging electrophile. Overall, this work expands the chemical space of peptide-based RC ligands, providing new synthetic and methodological tools to access selective, tunable covalent binders to target specific proteins or to inhibit clinically-relevant protein-protein interactions."]},{"key":"dc:title","label":"Title","values":["SALICYLALDEHYDE-TAGGED PEPTIDES FOR THE REVERSIBLE-COVALENT ENGAGEMENT OF PROTEIN LYSINE RESIDUES"]}]}],"canonical_facts":{"dc:contributor":["tutor: A. Dal Corso ; PhD coordinator: D. Passarella","M. Mason","DAL CORSO, ALBERTO","PASSARELLA, DANIELE"],"dc:creator":["MASON, MATTIA"],"dc:date":["2026-01-16"],"dc:description":["Covalent drug discovery has recently re-emerged as a powerful approach for targeting clinically-relevant proteins, offering enhanced potency and selectivity through controlled covalent interactions. In particular, reversible covalent (RC) chemistry combines the strength of covalent binding with the tunability of non-covalent interactions, mitigating the risks of permanent off-target reactivity. Within this context, this PhD thesis explores the use of salicylaldehyde (SA) as a reversible electrophilic warhead for peptide-based ligand design. The first part of this thesis focuses on the synthesis of SA-modified amino acids and their incorporation into model peptides. Later on, a more straightforward and versatile approach was devised, consisting in the late-stage peptide functionalization with copper-catalyzed azide- alkyne cycloaddition (CuAAC). This second strategy enabled efficient installation of SA moieties onto pre-assembled peptides specific for two protein targets, namely SHP2 and NEMO. Moreover, using human serum albumin as model target, the CuAAC protocol was instrumental for the design of a new combinatorial approach to SA-tagged small molecules. The final part of the work, carried out at the University of Tokyo, integrates SA-based reversible covalent chemistry into the RaPID (Random nonstandard Peptides Integrated Discovery) platform, paving the way to a novel strategy towards macrocyclic peptide libraries displaying a Lys-engaging electrophile. Overall, this work expands the chemical space of peptide-based RC ligands, providing new synthetic and methodological tools to access selective, tunable covalent binders to target specific proteins or to inhibit clinically-relevant protein-protein interactions."],"dc:identifier":["https://hdl.handle.net/2434/1205020"],"dc:language":["eng"],"dc:publisher":["Università degli Studi di Milano","place:Milan"],"dc:relation":["numberofpages:269"],"dc:rights":["info:eu-repo/semantics/embargoedAccess","license:Creative commons","license uri:http://creativecommons.org/licenses/by-sa/4.0/"],"dc:subject":["Settore CHEM-05/A - Chimica organica"],"dc:title":["SALICYLALDEHYDE-TAGGED PEPTIDES FOR THE REVERSIBLE-COVALENT ENGAGEMENT OF PROTEIN LYSINE RESIDUES"],"dc:type":["info:eu-repo/semantics/doctoralThesis"]},"updated_at":"2026-07-27T20:19:05Z"}