# Targeting the host NDP kinase to abrogate viral dissemination

> **NIH NIH R21** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2020 · $62,715

## Abstract

Project Summary
 There is an urgent and unmet need for the development of safe and effective therapeutics against serious
human pathogens such as Kaposi's sarcoma herpesvirus (KSHV), which causes significant morbidity and
mortality in immune-compromised individuals and remains a clinical challenge. Currently, no FDA approved
therapeutics or vaccines are available for KSHV infection. Given that KSHV and other human herpesviruses
hijack host proteins and pathways to complete their replication cycles and spread from cell to cell, strategies
targeting these pathways and mechanisms will provide broad-spectrum genotype coverage and a high barrier
to drug resistance. Herpesviruses including KSHV have long been known to exploit the COPII-mediated
secretory pathway for their maturation. However, the mechanisms governing this process remain less
understood. This project will fill this gap, capitalizing on our recent discovery that the host nucleoside
diphosphates kinase NM23-H2, an important regulator of COPII vesicle transport, is exploited by KSHV for
their virion morphogenesis and egress. We found that viral Bcl-2 of KSHV (ks-Bcl-2) directly interacted with,
stabilized, and activated NM23-H2 during lytic phase of KSHV. Loss of NM23-H2 or mutations in ks-Bcl-2 that
abolished NM23-H2 interaction severely impaired virion production. We thus hypothesize that KSHV activates
host protein NM23-H2 to exploit the COPII pathway for efficient virion assembly and release, unraveling
a key checkpoint in virus lifecycle that can be targeted for new antiviral therapeutics. We now bring
within this proposal a collaboration of experts in KSHV biology and in design of small-molecule inhibitors to
identify cellular pathway responsible for virion production of KSHV and develop a new strategy to dampen virus
transmission. To achieve this goal, we propose two specific aims, including (1) defining the molecular
mechanism by which KSHV ks-Bcl-2 targets NM23-H2 to activate Sar1-mediated COPII transport for efficient
virion assembly; and (2) targeting ks-Bcl-2-NM23-H2-mediated COPII mechanism to block KSHV propagation.
These aims will be addressed using multidisciplinary approaches that integrate state-of-the-art genetic,
biochemistry, live-cell imaging, and physiological assays. Together, we anticipate that our studies will identify
host genes/pathways that function in virus assembly and egress, and provide compelling in vivo validation that
targeting NM23-H2-dependent host mechanism can abrogate virus transmission within and between
individuals.

## Key facts

- **NIH application ID:** 9844941
- **Project number:** 5R21DE028256-02
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Pinghui Feng
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $62,715
- **Award type:** 5
- **Project period:** 2019-01-04 → 2020-06-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9844941

## Citation

> US National Institutes of Health, RePORTER application 9844941, Targeting the host NDP kinase to abrogate viral dissemination (5R21DE028256-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9844941. Licensed CC0.

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