| Full text | |
| Author(s): |
Cianni, Lorenzo
[1, 2, 3]
;
Feldmann, Christian Wolfgang
[1]
;
Gilberg, Erik
[1, 2]
;
Guetschow, Michael
[2]
;
Juliano, Luiz
[4, 5]
;
Leitao, Andrei
[3]
;
Bajorath, Juergen
[1]
;
Montanari, Carlos A.
[3]
Total Authors: 8
|
| Affiliation: | [1] Rhein Friedrich Wilhelms Univ, LIMES Program Unit Chem Biol & Med Chem, B IT, Dept Life Sci Informat, Endenicher Allee 19C, D-53115 Bonn - Germany
[2] Univ Bonn, Pharmaceut Chem 1, Pharmaceut Inst, Immenburg 4, D-53121 Bonn - Germany
[3] Univ Sao Paulo, Inst Chem Sao Carlos, Med Chem Grp, Ave Trabalhador Sancarlense 400, BR-23566590 Sao Carlos, SP - Brazil
[4] Univ Fed Sao Paulo, AC Camargo Canc Ctr, Rua Prof Antonio Prudente 211, BR-01509010 Sao Paulo, SP - Brazil
[5] Univ Fed Sao Paulo, Sao Paulo Med Sch, Rua Prof Antonio Prudente 211, BR-01509010 Sao Paulo, SP - Brazil
Total Affiliations: 5
|
| Document type: | Journal article |
| Source: | Journal of Medicinal Chemistry; v. 62, n. 23, p. 10497-10525, DEC 12 2019. |
| Web of Science Citations: | 1 |
| Abstract | |
Cysteine proteases are important targets for the discovery of novel therapeutics for many human diseases. From parasitic diseases to cancer, cysteine proteases follow a common mechanism, the formation of an encounter complex with subsequent nucleophilic reactivity of the catalytic cysteine thiol group toward the carbonyl carbon of a peptide bond or an electrophilic group of an inhibitor. Modulation of target enzymes occurs preferably by covalent modification, which imposes challenges in balancing cross-reactivity and selectivity. Given the resurgence of irreversible covalent inhibitors, can they impair off-target effects or are reversible covalent inhibitors a better route to selectivity? This Perspective addresses how small molecule inhibitors may achieve selectivity for different cathepsins, cruzain, rhodesain, and falcipain-2. We discuss target- and ligand-based designs emphasizing repurposing inhibitors from one cysteine protease to others. (AU) | |
| FAPESP's process: | 13/18009-4 - Molecular design, synthesis and trypanocidal activity of cruzain reversible covalent inhibitors |
| Grantee: | Carlos Alberto Montanari |
| Support Opportunities: | Research Projects - Thematic Grants |
| FAPESP's process: | 16/07946-5 - Synthesis and evaluation of trypanocidal activity of potential reversible covalent inhibitors of cruzain enzyme |
| Grantee: | Lorenzo Cianni |
| Support Opportunities: | Scholarships in Brazil - Doctorate (Direct) |