DP1AI169444

Defining the Viral PTMome: Towards the Development of Novel Antiviral Approaches - Project Summary

Over the past several decades, the traditional approach to combating viral infectious diseases has been to target the virus itself. In most cases, this involves blocking virus-encoded enzymes that are required for viral replication or preventing the virus from entering host cells. However, a major drawback of these approaches is the virus's ability to readily mutate and become resistant to classical types of antiviral therapies. This poses a serious problem for RNA virus infections, such as HIV or influenza virus, which are known to rapidly mutate and escape antiviral drugs.

Additionally, traditional antiviral approaches are designed to target specific viruses, making them ineffective against any new virus that may emerge in the future. It is impossible to predict what virus will cause the next outbreak or pandemic. Therefore, there is an urgent need to develop new ways of targeting viral pathogens, which will require creative and innovative research.

Like human proteins, viral proteins undergo posttranslational modifications (PTMs) for their regulation and proper functioning in the virus life cycle. In most cases, viral PTMs are dynamically regulated by human enzymes, such as kinases/phosphatases, ubiquitin E3 ligases/deubiquitinating enzymes, or acetyl transferases/deacetylases. Cellular enzymes play an important role in controlling the ability of the virus to replicate and cause disease.

The overarching goal of this proposal is to comprehensively map the 'viral PTMome' to identify the PTMs that are essential for virus replication and pathogenesis. This will be achieved by combining proteomics screens and molecular virology approaches, including reverse genetics techniques, with cutting-edge molecular, biochemical, and biophysical studies. Through this approach, we will identify and characterize viral PTMs and the responsible host modifying enzymes, as well as determine their roles in effective viral replication and pathogenesis.

Furthermore, we will collaborate with other researchers to design and test chemical inhibitors that can block the enzymes responsible for regulating critical viral PTMs. This powerful approach will not only provide unique mechanistic insight into host control of virus replication but also lay the groundwork for developing new antivirals for a range of emerging viral infectious diseases.

Cleveland Clinic Lerner College Of Medicine Of Case Western Reserve University

NOT APPLICABLE

93.310 - Trans-NIH Research Support

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Cleveland, Ohio 44195 United States

Single Zip Code

NIH Directors Pioneer Award Program (DP1 Clinical Trial Optional) (RFA-RM-20-011)

Amendment Since initial award the total obligations have increased 400% from $1,127,000 to $5,635,000.