bioTCIs: Middle-to-Macro Biomolecular Targeted Covalent Inhibitors Possessing Both Semi-Permanent Drug Action and Stringent Target Specificity as Potential Antibody Replacements
Monoclonal antibody therapies targeting immuno-modulatory targets such as checkpoint proteins, chemokines, and cytokines have made significant impact in several areas, including cancer, inflammatory disease, and infection. However, antibodies are complex biologics with well-known limitations, includ...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-02-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/4/3525 |
| _version_ | 1797620536723898368 |
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| author | Jay Yang Yudai Tabuchi Riku Katsuki Masumi Taki |
| author_facet | Jay Yang Yudai Tabuchi Riku Katsuki Masumi Taki |
| author_sort | Jay Yang |
| collection | DOAJ |
| description | Monoclonal antibody therapies targeting immuno-modulatory targets such as checkpoint proteins, chemokines, and cytokines have made significant impact in several areas, including cancer, inflammatory disease, and infection. However, antibodies are complex biologics with well-known limitations, including high cost for development and production, immunogenicity, a limited shelf-life because of aggregation, denaturation, and fragmentation of the large protein. Drug modalities such as peptides and nucleic acid aptamers showing high-affinity and highly selective interaction with the target protein have been proposed alternatives to therapeutic antibodies. The fundamental limitation of short in vivo half-life has prevented the wide acceptance of these alternatives. Covalent drugs, also known as targeted covalent inhibitors (TCIs), form permanent bonds to target proteins and, in theory, eternally exert the drug action, circumventing the pharmacokinetic limitation of other antibody alternatives. The TCI drug platform, too, has been slow in gaining acceptance because of its potential prolonged side-effect from off-target covalent binding. To avoid the potential risks of irreversible adverse drug effects from off-target conjugation, the TCI modality is broadening from the conventional small molecules to larger biomolecules possessing desirable properties (e.g., hydrolysis resistance, drug-action reversal, unique pharmacokinetics, stringent target specificity, and inhibition of protein–protein interactions). Here, we review the historical development of the TCI made of bio-oligomers/polymers (i.e., peptide-, protein-, or nucleic-acid-type) obtained by rational design and combinatorial screening. The structural optimization of the reactive warheads and incorporation into the targeted biomolecules enabling a highly selective covalent interaction between the TCI and the target protein is discussed. Through this review, we hope to highlight the middle to macro-molecular TCI platform as a realistic replacement for the antibody. |
| first_indexed | 2024-03-11T08:42:56Z |
| format | Article |
| id | doaj.art-65370de06ff043bb939e6ac3765904c3 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T08:42:56Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-65370de06ff043bb939e6ac3765904c32023-11-16T21:01:13ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-02-01244352510.3390/ijms24043525bioTCIs: Middle-to-Macro Biomolecular Targeted Covalent Inhibitors Possessing Both Semi-Permanent Drug Action and Stringent Target Specificity as Potential Antibody ReplacementsJay Yang0Yudai Tabuchi1Riku Katsuki2Masumi Taki3Department of Engineering Science, Graduate School of Informatics and Engineering, University of Electro-Communications (UEC), 1-5-1 Chofugaoka, Chofu 182-8585, JapanDepartment of Engineering Science, Graduate School of Informatics and Engineering, University of Electro-Communications (UEC), 1-5-1 Chofugaoka, Chofu 182-8585, JapanDepartment of Engineering Science, Graduate School of Informatics and Engineering, University of Electro-Communications (UEC), 1-5-1 Chofugaoka, Chofu 182-8585, JapanDepartment of Engineering Science, Graduate School of Informatics and Engineering, University of Electro-Communications (UEC), 1-5-1 Chofugaoka, Chofu 182-8585, JapanMonoclonal antibody therapies targeting immuno-modulatory targets such as checkpoint proteins, chemokines, and cytokines have made significant impact in several areas, including cancer, inflammatory disease, and infection. However, antibodies are complex biologics with well-known limitations, including high cost for development and production, immunogenicity, a limited shelf-life because of aggregation, denaturation, and fragmentation of the large protein. Drug modalities such as peptides and nucleic acid aptamers showing high-affinity and highly selective interaction with the target protein have been proposed alternatives to therapeutic antibodies. The fundamental limitation of short in vivo half-life has prevented the wide acceptance of these alternatives. Covalent drugs, also known as targeted covalent inhibitors (TCIs), form permanent bonds to target proteins and, in theory, eternally exert the drug action, circumventing the pharmacokinetic limitation of other antibody alternatives. The TCI drug platform, too, has been slow in gaining acceptance because of its potential prolonged side-effect from off-target covalent binding. To avoid the potential risks of irreversible adverse drug effects from off-target conjugation, the TCI modality is broadening from the conventional small molecules to larger biomolecules possessing desirable properties (e.g., hydrolysis resistance, drug-action reversal, unique pharmacokinetics, stringent target specificity, and inhibition of protein–protein interactions). Here, we review the historical development of the TCI made of bio-oligomers/polymers (i.e., peptide-, protein-, or nucleic-acid-type) obtained by rational design and combinatorial screening. The structural optimization of the reactive warheads and incorporation into the targeted biomolecules enabling a highly selective covalent interaction between the TCI and the target protein is discussed. Through this review, we hope to highlight the middle to macro-molecular TCI platform as a realistic replacement for the antibody.https://www.mdpi.com/1422-0067/24/4/3525covalent aptamerprotease/nuclease resistancewarheadmiddle-molecule covalent drugpeptide/oligonucleotide therapeuticsreactivity and affinity-based co-selection |
| spellingShingle | Jay Yang Yudai Tabuchi Riku Katsuki Masumi Taki bioTCIs: Middle-to-Macro Biomolecular Targeted Covalent Inhibitors Possessing Both Semi-Permanent Drug Action and Stringent Target Specificity as Potential Antibody Replacements International Journal of Molecular Sciences covalent aptamer protease/nuclease resistance warhead middle-molecule covalent drug peptide/oligonucleotide therapeutics reactivity and affinity-based co-selection |
| title | bioTCIs: Middle-to-Macro Biomolecular Targeted Covalent Inhibitors Possessing Both Semi-Permanent Drug Action and Stringent Target Specificity as Potential Antibody Replacements |
| title_full | bioTCIs: Middle-to-Macro Biomolecular Targeted Covalent Inhibitors Possessing Both Semi-Permanent Drug Action and Stringent Target Specificity as Potential Antibody Replacements |
| title_fullStr | bioTCIs: Middle-to-Macro Biomolecular Targeted Covalent Inhibitors Possessing Both Semi-Permanent Drug Action and Stringent Target Specificity as Potential Antibody Replacements |
| title_full_unstemmed | bioTCIs: Middle-to-Macro Biomolecular Targeted Covalent Inhibitors Possessing Both Semi-Permanent Drug Action and Stringent Target Specificity as Potential Antibody Replacements |
| title_short | bioTCIs: Middle-to-Macro Biomolecular Targeted Covalent Inhibitors Possessing Both Semi-Permanent Drug Action and Stringent Target Specificity as Potential Antibody Replacements |
| title_sort | biotcis middle to macro biomolecular targeted covalent inhibitors possessing both semi permanent drug action and stringent target specificity as potential antibody replacements |
| topic | covalent aptamer protease/nuclease resistance warhead middle-molecule covalent drug peptide/oligonucleotide therapeutics reactivity and affinity-based co-selection |
| url | https://www.mdpi.com/1422-0067/24/4/3525 |
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