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.
Highlights
We tested the 10 peptoids shown in Figure 1B for activity against Herpes Simplex Virus-1 (HSV-1)
This was accomplished by incubating the virus with the peptoid at 20 μg/mL for 2 h at 37 ◦ C, prior to using the incubated virus to infect cultures of OKF6/TERT-1 cells
Due to the mechanisms of infection and pathogenesis at play, it has been difficult to design any efmechanisms and pathogenesis play, it has other beenpreventive difficult to design fective vaccinesoftoinfection prevent herpesvirus infections.atFurthermore, and pal- any efliative methods have challenging to adapt to broad clinical use
Summary
Herpes simplex virus type-1 (HSV-1) infections cause recurrent oral lesions in the developed world, and are the primary cause of infectious blindness and genital infections. Pharmaceuticals 2021, 14, 304 in developed countries. HSV-1 infections can be life-threatening in immunocompromised individuals [1]. There is recent evidence that HSV-1 infections are associated with the pathogenesis of Alzheimer’s disease [2]. The HSV-1 virus is transmitted readily through oral secretions. The primary class of antiviral therapeutics for this pathogen are nucleoside analogues, such as acyclovir or its pro-drug valacyclovir. There is evidence of the development of resistance to this class of antivirals, especially in immunocompromised individuals [5]
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