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.

BACKGROUND: Hereditary alpha-tryptasemia (HαT) is characterized by elevated basal serum tryptase due to increased copies of the TPSAB1 gene. Individuals with HαT frequently present with multisystem complaints, including anaphylaxis and seemingly functional gastrointestinal (GI) symptoms. OBJECTIVE: We sought to determine the prevalence of HαT in an irritable bowel syndrome cohort and associated immunologic characteristics that may distinguish patients with HαT from patients without HαT. METHODS: Tryptase genotyping by droplet digital PCR, flow cytometry, cytometry by time-of-flight, immunohistochemistry, and other molecular biology techniques was used. RESULTS: HαT prevalence in a large irritable bowel syndrome cohort was 5% (N = 8/158). Immunophenotyping of HαT PBMCs (N ≥ 27) revealed increased total and class-switched memory B cells. In the small bowel, expansion of tissue mast cells with expression of CD203c, HLA-DR, and FcεRI, higher intestinal epithelial cell pyroptosis, and increased class-switched memory B cells were observed. IgG profiles in sera from individuals with HαT (N = 21) significantly differed from those in individuals with quiescent Crohn disease (N = 20) and non-HαT controls (N = 19), with increased antibodies directed against GI-associated proteins identified in individuals with HαT. CONCLUSIONS: Increased mast cell number and intestinal epithelial cell pyroptosis in the small intestine, and class-switched memory B cells in both the gut and peripheral blood associated with IgG reactive to GI-related proteins, distinguish HαT from functional GI disease. These innate and adaptive immunologic findings identified in association with HαT are suggestive of subclinical intestinal inflammation in symptomatic individuals.