Medicinal chemistry strategies for discovering antivirals effective against drug-resistant viruses
| Autor: | Yue Ma, Luis Menéndez-Arias, Dongwei Kang, Xinyong Liu, Erik De Clercq, Christophe Pannecouque, Estrella Frutos-Beltrán, Peng Zhan |
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| Přispěvatelé: | National Natural Science Foundation of China, Ministerio de Ciencia e Innovación (España), Fundación Ramón Areces |
| Rok vydání: | 2021 |
| Předmět: |
Drug
0303 health sciences 030306 microbiology Drug discovery medicine.drug_class Chemistry Pharmaceutical media_common.quotation_subject Covalent binding Microbial Sensitivity Tests General Chemistry Drug resistance Protein degradation Antiviral Agents Medicinal chemistry 03 medical and health sciences Drug Discovery Drug Resistance Viral Viruses Dihydroorotate dehydrogenase medicine Multivalent binding Antiviral drug 030304 developmental biology media_common |
| Popis: | During the last forty years we have witnessed impressive advances in the field of antiviral drug discovery culminating with the introduction of therapies able to stop human immunodeficiency virus (HIV) replication, or cure hepatitis C virus infections in people suffering from liver disease. However, there are important viral diseases without effective treatments, and the emergence of drug resistance threatens the efficacy of successful therapies used today. In this review, we discuss strategies to discover antiviral compounds specifically designed to combat drug resistance. Currently, efforts in this field are focused on targeted proteins (e.g. multi-target drug design strategies), but also on drug conformation (either improving drug positioning in the binding pocket or introducing conformational constraints), in the introduction or exploitation of new binding sites, or in strengthening interaction forces through the introduction of multiple hydrogen bonds, covalent binding, halogen bonds, additional van der Waals forces or multivalent binding. Among the new developments, proteolysis targeting chimeras (PROTACs) have emerged as a valid approach taking advantage of intracellular mechanisms involving protein degradation by the ubiquitin-proteasome system. Finally, several molecules targeting host factors (e.g. human dihydroorotate dehydrogenase and DEAD-box polypeptide 3) have been identified as broad-spectrum antiviral compounds. Implementation of herein described medicinal chemistry strategies are expected to contribute to the discovery of new drugs effective against current and future threats due to emerging and re-emerging viral pandemics. This journal is National Natural Science Foundation of China; Ministry of Science and Innovation of Spain (BIO2016-76716-R (AEI/FEDER, UE)) and (PID2019-104176RB-I00/AEI/10.13039/501100011033) and CSIC (2019AEP001), as well as an institutional grant of Fundació Ramón Areces awarded to the CBMSO |
| Databáze: | OpenAIRE |
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