Covalent Reversible Inhibitors of Cysteine Proteases Containing the Nitrile Warhead: Recent Advancement in the Field of Viral and Parasitic Diseases
In the field of drug discovery, the nitrile group is well represented among drugs and biologically active compounds. It can form both non-covalent and covalent interactions with diverse biological targets, and it is amenable as an electrophilic warhead for covalent inhibition. The main advantage of...
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MDPI AG
2022-04-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/27/8/2561 |
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| author | Simone Brogi Roberta Ibba Sara Rossi Stefania Butini Vincenzo Calderone Sandra Gemma Giuseppe Campiani |
| author_facet | Simone Brogi Roberta Ibba Sara Rossi Stefania Butini Vincenzo Calderone Sandra Gemma Giuseppe Campiani |
| author_sort | Simone Brogi |
| collection | DOAJ |
| description | In the field of drug discovery, the nitrile group is well represented among drugs and biologically active compounds. It can form both non-covalent and covalent interactions with diverse biological targets, and it is amenable as an electrophilic warhead for covalent inhibition. The main advantage of the nitrile group as a warhead is mainly due to its milder electrophilic character relative to other more reactive groups (e.g., -CHO), reducing the possibility of unwanted reactions that would hinder the development of safe drugs, coupled to the ease of installation through different synthetic approaches. The covalent inhibition is a well-assessed design approach for serine, threonine, and cysteine protease inhibitors. The mechanism of hydrolysis of these enzymes involves the formation of a covalent acyl intermediate, and this mechanism can be exploited by introducing electrophilic warheads in order to mimic this covalent intermediate. Due to the relevant role played by the cysteine protease in the survival and replication of infective agents, spanning from viruses to protozoan parasites, we will review the most relevant and recent examples of protease inhibitors presenting a nitrile group that have been introduced to form or to facilitate the formation of a covalent bond with the catalytic cysteine active site residue. |
| first_indexed | 2024-03-09T10:31:32Z |
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| id | doaj.art-d8cf81a8f50249849730be6dcae563b2 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T10:31:32Z |
| publishDate | 2022-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-d8cf81a8f50249849730be6dcae563b22023-12-01T21:16:21ZengMDPI AGMolecules1420-30492022-04-01278256110.3390/molecules27082561Covalent Reversible Inhibitors of Cysteine Proteases Containing the Nitrile Warhead: Recent Advancement in the Field of Viral and Parasitic DiseasesSimone Brogi0Roberta Ibba1Sara Rossi2Stefania Butini3Vincenzo Calderone4Sandra Gemma5Giuseppe Campiani6Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, ItalyDepartment of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, University of Siena, Via Aldo Moro 2, 53100 Siena, ItalyDepartment of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, University of Siena, Via Aldo Moro 2, 53100 Siena, ItalyDepartment of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, University of Siena, Via Aldo Moro 2, 53100 Siena, ItalyDepartment of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, ItalyDepartment of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, University of Siena, Via Aldo Moro 2, 53100 Siena, ItalyDepartment of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, University of Siena, Via Aldo Moro 2, 53100 Siena, ItalyIn the field of drug discovery, the nitrile group is well represented among drugs and biologically active compounds. It can form both non-covalent and covalent interactions with diverse biological targets, and it is amenable as an electrophilic warhead for covalent inhibition. The main advantage of the nitrile group as a warhead is mainly due to its milder electrophilic character relative to other more reactive groups (e.g., -CHO), reducing the possibility of unwanted reactions that would hinder the development of safe drugs, coupled to the ease of installation through different synthetic approaches. The covalent inhibition is a well-assessed design approach for serine, threonine, and cysteine protease inhibitors. The mechanism of hydrolysis of these enzymes involves the formation of a covalent acyl intermediate, and this mechanism can be exploited by introducing electrophilic warheads in order to mimic this covalent intermediate. Due to the relevant role played by the cysteine protease in the survival and replication of infective agents, spanning from viruses to protozoan parasites, we will review the most relevant and recent examples of protease inhibitors presenting a nitrile group that have been introduced to form or to facilitate the formation of a covalent bond with the catalytic cysteine active site residue.https://www.mdpi.com/1420-3049/27/8/2561nitrilewarheadcysteine/serine/threonine proteasevirusprotozoan parasitecovalent inhibition |
| spellingShingle | Simone Brogi Roberta Ibba Sara Rossi Stefania Butini Vincenzo Calderone Sandra Gemma Giuseppe Campiani Covalent Reversible Inhibitors of Cysteine Proteases Containing the Nitrile Warhead: Recent Advancement in the Field of Viral and Parasitic Diseases Molecules nitrile warhead cysteine/serine/threonine protease virus protozoan parasite covalent inhibition |
| title | Covalent Reversible Inhibitors of Cysteine Proteases Containing the Nitrile Warhead: Recent Advancement in the Field of Viral and Parasitic Diseases |
| title_full | Covalent Reversible Inhibitors of Cysteine Proteases Containing the Nitrile Warhead: Recent Advancement in the Field of Viral and Parasitic Diseases |
| title_fullStr | Covalent Reversible Inhibitors of Cysteine Proteases Containing the Nitrile Warhead: Recent Advancement in the Field of Viral and Parasitic Diseases |
| title_full_unstemmed | Covalent Reversible Inhibitors of Cysteine Proteases Containing the Nitrile Warhead: Recent Advancement in the Field of Viral and Parasitic Diseases |
| title_short | Covalent Reversible Inhibitors of Cysteine Proteases Containing the Nitrile Warhead: Recent Advancement in the Field of Viral and Parasitic Diseases |
| title_sort | covalent reversible inhibitors of cysteine proteases containing the nitrile warhead recent advancement in the field of viral and parasitic diseases |
| topic | nitrile warhead cysteine/serine/threonine protease virus protozoan parasite covalent inhibition |
| url | https://www.mdpi.com/1420-3049/27/8/2561 |
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