Dual Anti-Inflammatory and Antiviral Strategy to Combat COVID-19
Abstract
The SARS-CoV-2 virus is responsible for the deadly COVID-19 disease that infected over 2 million Americans. As of today, there is still no effective medicine to combat this illness. There are 115,000 confirmed deaths at the time of writing. The proposed work offers an effective medical treatment to oppress symptoms and illness, as such shall significantly reduce suffering and accelerate recovery. The mechanism of infection and the human body’s immune responses provide rationale for our approach. People catch COVID-19 when they inhale particles expelled from an infected person’s speech, cough, or sneeze. Once inhaled, the virus infects cells in the airway and takes over or “hijacks” cellular machinery to make many new virus copies, which then infect nearby cells. This process repeats and the virus spreads from the upper airway (sinus, nose, throat) into the windpipe and then deep into the lungs and beyond. The body defends itself by mounting a massive immune response to kill the virus and virus-infected cells. The process of mounting the immune response includes turning on cellular machinery to make new copies of inflammatory genes that help kill the virus. Unfortunately, this massive immune response can cause collateral damage to healthy cells and tissues. When this happens in the lungs, it is called acute respiratory distress syndrome (ARDS), and this can cause permanent lung scarring (fibrosis) or even death. At first glance, the process of virus spreading might seem unrelated to the process of mounting an immune response against the virus. Yet both processes involve making new copies of genes, either viral genes or inflammatory genes. In fact, with previous Peer Reviewed Medical Research Program (PRMRP) funding, we discovered that the exact same protein “hijacked” by the virus to make copies of itself is also absolutely necessary to activate inflammatory genes. This dual-activity protein is called Cdk9. With previous and ongoing PRMRP funding, we are developing an anti-inflammatory therapeutic using a Cdk9 inhibitor drug called flavopiridol that inactivates Cdk9. The rationale supporting this project is that while inhibitors of Cdk9 are known to prevent virus replication, and separately, inhibitors of Cdk9 are also known to prevent inflammation, no one has ever tested whether Cdk9 inhibitors can prevent both viral replication and inflammation at the same time. Our first objective is to firmly establish that the Cdk9 inhibitor flavopiridol will prevent both SARS-CoV-2 virus replication and inflammation at the same time in mouse models. Because a successful outcome is very likely, our second objective includes making an inhaled version of flavopiridol to deliver it directly to the lungs where the SARS-CoV-2 virus is most active. Our hypothesis is that inhibiting both functions of Cdk9 with flavopiridol will benefit patients by slowing virus spreading and by reducing the massive immune response, which together will prevent many of the downstream complications such as ARDS and fibrosis. Our project addresses the FY20 PRMRP Topic Area of Respiratory Health, and Focus Areas “Pharmacological interventions for COVID-19 induced complications including ARDS and related sequelae” and “Novel innovative therapeutics to reduce the incidence or severity of ARDS and other lung injury secondary to coronaviruses.” The project also addresses the Topic Area of Emerging Viral Diseases because most types of virus hijack Cdk9 protein to make new virus, so the same therapeutic strategy can help combat future viral pandemics. Our research will lead to the development of a dual therapeutic strategy that is both anti-viral and anti-inflammatory. It will directly benefit patients who are infected by the SARS-CoV-2 virus by reducing the severity of the COVID-19 disease, by increasing patient survival, and by limiting the harmful lung inflammation and fibrosis secondary to the infection. The Cdk9 inhibitor flavopi
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110015
Entities
People
- Dominik R Haudenschild
Organizations
- United States Army
- University of California, Davis