# Dissecting the mechanism of herpesvirus genome packaging

> **NIH NIH DP2** · YALE UNIVERSITY · 2024 · $42,979

## Abstract

PROJECT SUMMARY
Human herpesviruses can cause congenital birth defects in neonates and a wide range of disease in humans,
with particularly devastating effects in immunocompromised individuals. Kaposi's sarcoma-associated
herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma and other cancers, with high prevalence in sub-
Saharan Africa. There is no cure for any herpesvirus; most existing antivirals target a single viral process and
can lead to resistance mutations. The recent development of a herpesviral packaging inhibitor highlights the
viral genome packaging machinery as an attractive target for novel antivirals. The herpesviral packaging
machinery is conceptually similar to that of bacteriophages, yet it has additional complexities that include
factors of unknown function. In this proposal, I outline my vision to understand the molecular mechanism of
herpesvirus packaging. I will determine the function of an essential factor in herpesvirus packaging that has
long evaded mechanistic dissection using state-of-the-art proteomics and microscopy approaches. I will also
develop a new strategy to apply deep mutational scanning approaches to herpesviral proteins. In parallel, I will
determine the structure of the KSHV terminase, the viral molecular motor that packages the viral genome into
the nascent capsid. I will then reconstitute the essential components of the KSHV packaging machinery and
use these to develop an in vitro packaging assay. This assay will be leveraged to screen for new antivirals and
determine the molecular underpinnings of existing drugs that target the packaging machinery. The proposed
studies will build a foundation to address long-standing, fundamental questions in DNA virus packaging and
understand the mechanism of anti-herpesvirals.

## Key facts

- **NIH application ID:** 11066034
- **Project number:** 3DP2AI171113-03S1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Allison Louise Didychuk
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $42,979
- **Award type:** 3
- **Project period:** 2022-08-25 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11066034

## Citation

> US National Institutes of Health, RePORTER application 11066034, Dissecting the mechanism of herpesvirus genome packaging (3DP2AI171113-03S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/11066034. Licensed CC0.

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