# NIH grant: Mechanistic characterization and rational design of Lassa virus entry inhibitors (1R21AI193680-01A1) — retained record

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[original source ↗](https://reporter.nih.gov/project-details/1R21AI193680-01A1)

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NIH grant 1R21AI193680-01A1: Mechanistic characterization and rational design of Lassa virus entry inhibitors
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: Huihui  Mu. Award: $282250.
Start: 2026-08-07T00:00:00.
PROJECT SUMMARY
Lassa virus (LASV), a BSL-4 pathogen and the causative agent of Lassa fever, poses a significant public health
threat due to its epidemic potential both within and outside endemic regions and the lack of FDA-approved
treatments or vaccines. The LASV glycoprotein complex (GPC), the sole envelope-anchored viral protein, and
the entry process it mediates are key targets for developing intervention strategies. Despite extensive efforts,
progress on vaccines and immunotherapies has been impeded by glycosylation of GPC, the genetic diversity of
LASV, and the cost and time required for these strategies. Small-molecule arenavirus inhibitors have shown
promise, but further development has been limited by poor target specificity and a lack of mechanistic insight.
These challenges raise a critical question: how can we accelerate the development of effective, accessible LASV
therapeutics suitable for broad use, particularly in resource-limited endemic regions?
To address this unmet need, we conducted two parallel screens of a 665,000-compound library, controlled by
SARS-CoV-2 and Machupo virus, respectively, and identified a family of small-molecule entry inhibitors that are
non-toxic, potent, and specific for LASV entry, with pan-lineage activity. To the best of our knowledge, these
compounds are the first to inhibit LASV entry without targeting other arenaviruses. Preliminary mechanistic
studies suggest their direct interactions with the membrane-proximal region of LASV GPC, indicating a potential
mechanism for disrupting conformational changes required for secondary receptor engagement or subsequent
membrane fusion. Additionally, these inhibitors exhibit encouraging drug-like properties in both in vitro and in
vivo drug metabolism and pharmacokinetics (DMPK) studies. Our initial structure-activity relationship (SAR)
analyses support their potential for further optimization towards clinical development.
In this proposal, we will develop these LASV-specific entry inhibitors through two independent and synergistic
approaches. In Aim 1, we will investigate how these compounds interact with LASV GPC and inhibit viral entry.
This effort will reveal the antiviral mechanisms of our lead compounds and inform targets for future LASV-specific
antiviral design. In Aim 2, we will further optimize their antiviral efficacy and drug-likeness through detailed SAR
and DMPK studies. Together, these studies will advance first-in-class LASV-specific small-molecule therapeutics
and establish a robust platform for antiviral discovery against high-priority emerging pathogens.
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