Award Abstract #2031094

RAPID: Host-pathogen interactions during genome replication of SARS-CoV2

NSF Directorate:
BIO - Directorate for Biological Sciences
NSF Division:

Division of Molecular and Cellular Biosciences

Initial Amendment Date:

Latest Amendment Date:

Award Number:

2031094

Award Instrument:

Grant

Program Manager:

Manju Hingorani

Start Date:

End Date:

Awarded Amount to Date:

$162,283.00

Investigator(s):

Taekjip Ha [email protected] (Principal Investigator)
James M Berger (Co-Principal Investigator)

Sponsor:

Johns Hopkins University
1101 E 33rd St
Baltimore MD 212182686

NSF Program:
Genetic Mechanisms
COVID-19 Research
Program Reference Code(s):
096Z
7465
7914
Program Element Code(s):
158Y
Abstract:

Replication of coronaviruses, including SARS-CoV-2 – the causative agent of COVID-19, is expected to involve protein factors from the infected host cell that provide activities not encoded in the viral genome. This project focuses on the need for the virus to co-opt a host 3’ to 5’ RNA helicase to synthesize the negative-strand RNA that serves as template for copying the positive-strand genome. A recent proteomic screen identified a candidate host helicase, DDX10, that interacts with SARS-CoV-2 proteins. The research will employ a suite of experimental approaches to characterize this enzyme and two other host RNA helicases also implicated in SARS-CoV-2 genome replication. Detailed knowledge of how host proteins contribute to viral replication will provide new targets for therapeutic intervention, importantly, in ways that help circumvent drug resistance through viral mutation. The project will also support training of a postdoctoral scholar and development of a new undergraduate biophysics course centered on coronavirus-related topics.

Biochemical and biophysical techniques, such as X-ray crystallography, cryo-EM and single molecule spectroscopy, will be applied to determine structure-function properties that govern the helicase mechanism, including polarity, speed, processivity and associated energetics, and how its interactions with the viral NSP7/8 primase influence genome replication. The outcomes are expected to reveal the workings of host proteins during SARS-CoV-2 replication, and thereby open new avenues and novel drug targets to block its proliferation.

This RAPID award is made by the Genetic Mechanisms Program in the Division of Molecular and Cellular Biosciences, using funds from the Coronavirus Aid, Relief, and Economic Security (CARES) Act.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.