# Targeting glycoprotein (G) domain-III for pan-lyssavirus nanobody therapeutics

> **NIH NIH UH2** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2024 · $195,000

## Abstract

Abstract
The lethal rabies encephalitis diseases are caused by members of the zoonotic lyssavirus genus. The high
genetic diversity separates lyssavirus members into three phylogroups, while cross-phylogroup (especially to
phylogroups 2 and 3) protection has not been established by current post-exposure prophylaxis (PEP) or
antibody therapeutics. To achieve more broadly effective countermeasures to rabies disease worldwide and to
prepare for the emergence of new lyssaviruses, effective therapeutic agents against all phylogroups are
necessary. Lyssavirus G glycoprotein is the sole antibody target on the virion surface, which adopt distinct
conformations between pre- and post- fusion states as other class-III viral fusion machineries. Domain-III of
lyssavirus G glycoprotein encompasses a large neutralizing antibody-accessible surface in the native state.
Sequence analysis on domain-III revealed several conserved patches across all phylogroups, which could
potentially serve as target epitopes for pan-lyssavirus neutralizers. Antigen-specific nanobodies have been
considered as promising therapeutic agents against various infectious diseases and non-infectious diseases,
which have the advantage in binding compact and hidden epitopes that are out of reach for conventional
antibodies. We hypothesized that by focusing immune recognition on the lyssavirus G domain-III conserved
epitopes, we can identify pan-lyssavirus neutralizing nanobodies for immunotherapeutics. In this study, we
propose two specific aims: (1) to use a structure-based and antibody-guided approach to design and characterize
the antigenicity of lyssavirus glycoprotein domain-III, a site of viral vulnerability targeted by several broadly
neutralizing antibodies, for revelation of the antibody neutralization mechanism; (2) to identify and characterize
pan-lyssavirus neutralizing nanobodies for therapeutics by focusing immune recognition on lyssavirus G domain
III conserved epitopes.

## Key facts

- **NIH application ID:** 10999144
- **Project number:** 7UH2AI171611-02
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Kai Xu
- **Activity code:** UH2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $195,000
- **Award type:** 7
- **Project period:** 2023-03-07 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10999144

## Citation

> US National Institutes of Health, RePORTER application 10999144, Targeting glycoprotein (G) domain-III for pan-lyssavirus nanobody therapeutics (7UH2AI171611-02). Retrieved via AI Analytics 2026-06-23 from https://api.ai-analytics.org/grant/nih/10999144. Licensed CC0.

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