University of Massachusetts Medical School Faculty Publications


Drug Design Strategies to Avoid Resistance in Direct-Acting Antivirals and Beyond

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology; Schiffer Lab; Graduate School of Biomedical Sciences

Publication Date


Document Type



Amino Acids, Peptides, and Proteins | Biochemistry | Medicinal Chemistry and Pharmaceutics | Medicinal-Pharmaceutical Chemistry | Pharmaceutics and Drug Design | Virus Diseases | Viruses


Drug 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.


Drug resistance, Viruses, Peptides and proteins, Genetics, Inhibitors

DOI of Published Version



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

Related Resources

Link to Article in PubMed

Journal/Book/Conference Title

Chemical reviews

PubMed ID