Potent Antiviral Activity against HSV-1 and SARS-CoV-2 by Antimicrobial Peptoids

Gill Diamond; Natalia Molchanova; Claudine Herlan; John A Fortkort; Jennifer S Lin; Erika Figgins; Nathen Bopp; Lisa K Ryan; Donghoon Chung; Robert Scott Adcock; Michael Sherman; Annelise E Barron

doi:10.3390/ph14040304

Potent Antiviral Activity against HSV-1 and SARS-CoV-2 by Antimicrobial Peptoids

Pharmaceuticals (Basel). 2021 Mar 31;14(4):304. doi: 10.3390/ph14040304.

Authors

Gill Diamond¹, Natalia Molchanova^{2

3}, Claudine Herlan^{2

4}, John A Fortkort², Jennifer S Lin^{2

3}, Erika Figgins¹, Nathen Bopp⁵, Lisa K Ryan⁶, Donghoon Chung⁷, Robert Scott Adcock⁷, Michael Sherman⁸, Annelise E Barron^{2

3}

Affiliations

¹ Department of Oral Immunology and Infectious Diseases, University of Louisville School of Dentistry, Louisville, KY 40202, USA.
² Department of Bioengineering, Stanford University School of Medicine, Stanford, CA 94305, USA.
³ Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
⁴ Institute of Organic Chemistry, Karlsruhe Institute of Technology, 76131 Karlsruhe, Germany.
⁵ Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA.
⁶ Division of Infectious Diseases and Global Medicine, Department of Medicine, University of Florida School of Medicine, Gainesville, FL 32601, USA.
⁷ Center for Predictive Medicine, Department of Microbiology, School of Medicine, University of Louisville, Louisville, KY 40202, USA.
⁸ Department of Biochemistry and Molecular Biology, Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, TX 77555, USA.

Abstract

Viral infections, such as those caused by Herpes Simplex Virus-1 (HSV-1) and SARS-CoV-2, affect millions of people each year. However, there are few antiviral drugs that can effectively treat these infections. The standard approach in the development of antiviral drugs involves the identification of a unique viral target, followed by the design of an agent that addresses that target. Antimicrobial peptides (AMPs) represent a novel source of potential antiviral drugs. AMPs have been shown to inactivate numerous different enveloped viruses through the disruption of their viral envelopes. However, the clinical development of AMPs as antimicrobial therapeutics has been hampered by a number of factors, especially their enzymatically labile structure as peptides. We have examined the antiviral potential of peptoid mimics of AMPs (sequence-specific N-substituted glycine oligomers). These peptoids have the distinct advantage of being insensitive to proteases, and also exhibit increased bioavailability and stability. Our results demonstrate that several peptoids exhibit potent in vitro antiviral activity against both HSV-1 and SARS-CoV-2 when incubated prior to infection. In other words, they have a direct effect on the viral structure, which appears to render the viral particles non-infective. Visualization by cryo-EM shows viral envelope disruption similar to what has been observed with AMP activity against other viruses. Furthermore, we observed no cytotoxicity against primary cultures of oral epithelial cells. These results suggest a common or biomimetic mechanism, possibly due to the differences between the phospholipid head group makeup of viral envelopes and host cell membranes, thus underscoring the potential of this class of molecules as safe and effective broad-spectrum antiviral agents. We discuss how and why differing molecular features between 10 peptoid candidates may affect both antiviral activity and selectivity.

Keywords: COVID-19; HSV-1; LL-37; SARS-CoV-2; air-liquid interface; antivirals; cytotoxicity; membrane disruption; peptoids.

Abstract

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