Drug Design Strategies to Avoid Resistance in Direct-Acting Antivirals and Beyond
AuthorsMatthew, Ashley N.
Lockbaum, Gordon J.
Desaboini, Nageswara Rao
Rusere, Linah N.
Ragland, Debra A.
Paulsen, Janet L.
Prachanronarong, Kristina L.
Soumana, Djade I.
Nalivaika, Ellen A.
Yilmaz, Nese Kurt
Schiffer, Celia A.
UMass Chan AffiliationsGraduate School of Biomedical Sciences
Department of Biochemistry and Molecular Pharmacology
Document TypeJournal Article
Peptides and proteins
Amino Acids, Peptides, and Proteins
Medicinal Chemistry and Pharmaceutics
Pharmaceutics and Drug Design
MetadataShow full item record
AbstractDrug resistance is prevalent across many diseases, rendering therapies ineffective with severe financial and health consequences. Rather than accepting resistance after the fact, proactive strategies need to be incorporated into the drug design and development process to minimize the impact of drug resistance. These strategies can be derived from our experience with viral disease targets where multiple generations of drugs had to be developed to combat resistance and avoid antiviral failure. Significant efforts including experimental and computational structural biology, medicinal chemistry, and machine learning have focused on understanding the mechanisms and structural basis of resistance against direct-acting antiviral (DAA) drugs. Integrated methods show promise for being predictive of resistance and potency. In this review, we give an overview of this research for human immunodeficiency virus type 1, hepatitis C virus, and influenza virus and the lessons learned from resistance mechanisms of DAAs. These lessons translate into rational strategies to avoid resistance in drug design, which can be generalized and applied beyond viral targets. While resistance may not be completely avoidable, rational drug design can and should incorporate strategies at the outset of drug development to decrease the prevalence of drug resistance.
Matthew AN, Leidner F, Lockbaum GJ, Henes M, Zephyr J, Hou S, Rao DN, Timm J, Rusere LN, Ragland DA, Paulsen JL, Prachanronarong K, Soumana DI, Nalivaika EA, Kurt Yilmaz N, Ali A, Schiffer CA. Drug Design Strategies to Avoid Resistance in Direct-Acting Antivirals and Beyond. Chem Rev. 2021 Jan 7. doi: 10.1021/acs.chemrev.0c00648. Epub ahead of print. PMID: 33410674. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/29668