Antiviral Activity and Mucosal Safety of Novel Human-Milk-Inspired Antimicrobial Peptides

Authors

• Nazita Yousefieh, Macon & Joan Brock Virginia Health Sciences at Old Dominion UniversityFollow
• Louise A. Ouattara, Macon & Joan Brock Virginia Health Sciences at Old Dominion UniversityFollow
• Maimoona Bhutta, Macon & Joan Brock Virginia Health Sciences at Old Dominion UniversityFollow
• Ishita M. Shah, University of California Davis
• Carolina Herrera, Macon & Joan Brock Virginia Health Sciences at Old Dominion University
• Gustavo F. Doncel, Macon & Joan Brock Virginia Health Sciences at Old Dominion UniversityFollow

ORCID

0009-0007-9374-6248 (Ouattara), 0000-0002-0057-8094 (Bhutta), 0000-0003-3701-752X (Herrera), 0009-0009-9641-1325 (Doncel)

Document Type

Article

Publication Date

2026

DOI

10.3390/pharmaceutics18080938

Publication Title

Pharmaceutics

Volume

18

Issue

8

Pages

938 (19 pp.)

Abstract

Background: Sexually transmitted infections (STIs) remain a major global health concern, with over one million new curable cases reported daily and limited long-term treatment options. Additionally, there are limited treatment options for women with bacterial vaginosis (BV), a dysbiotic condition predisposing them to STIs. Computationally designed human-milk-inspired antimicrobial peptides (AMPs) are promising candidates for novel antiviral and antibacterial therapies. This study evaluated the cervicovaginal mucosal safety and antiviral activity of three human-milk-inspired AMPs (MAT-006, UCD-MAT-001, and UCD-MAT-002) previously shown to exhibit antimicrobial activity against BV-causing pathogens. Methods: AMP cytotoxicity and inflammatory responses were assessed in relevant genital tract cell lines and cervicovaginal tissues in vitro. AMP anti-HIV-1 and anti-HSV-2 activities were characterized in female genital tract cell lines, TZM-bl cells and HEC-1-A cells, respectively, and in time-of-addition (pre-, co-, and post-HIV-1 challenge; and post-HSV-2 challenge) experiments. The impact of seminal plasma on AMPs' activity was also evaluated. Results: At the concentrations tested, all three AMPs showed minimal cytotoxicity and no pro-inflammatory responses in cellular and ectocervical tissue explant models. In both co- and post-exposure models, all three AMPs inhibited HIV-1 and HSV-2 replication with IC₅₀ values ranging from 0.78 to 7.72 mg/mL. MAT-006 further showed pre-exposure anti-HIV-1 activity after 6 h (IC₅₀ = 1.07 ± 0.515 mg/mL) and 24 h (IC₅₀ = 0.69 ± 0.152 mg/mL) of incubation. Seminal plasma did not significantly impair MAT-006 and UCD-MAT-001 antiviral activity under experimental conditions. Conclusions: These findings demonstrate the antiviral activity of human-milk-inspired AMPs against HIV-1 and HSV-2 at concentrations that are safe to the cervicovaginal mucosa in vitro, warranting further preclinical evaluation as microbicide candidates with dual antibacterial and antiviral properties.

Rights

© 2026 by the authors.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International (CC BY 4.0) License.

Data Availability

Article states: "Data are available upon request to the corresponding author."

Original Publication Citation

Yousefieh, N., Ouattara, L. A., Bhutta, M., Shah, I. M., Herrera, C., & Doncel, G. F. (2026). Antiviral activity and mucosal safety of novel human-milk-inspired antimicrobial peptides. Pharmaceutics, 18(8), Article 938. https://doi.org/10.3390/pharmaceutics18080938

Repository Citation

Yousefieh, N., Ouattara, L. A., Bhutta, M., Shah, I. M., Herrera, C., & Doncel, G. F. (2026). Antiviral activity and mucosal safety of novel human-milk-inspired antimicrobial peptides. Pharmaceutics, 18(8), Article 938. https://doi.org/10.3390/pharmaceutics18080938