Development of Small Molecules to Mitigate the SARS-CoV-2 Cytokine Storm
Dr. Don L. Warner
SARS-CoV-2 was the third leading cause of death in 2020, with a fatality rate of 1.8% in the United States. While vaccines will overcome the novel coronavirus crisis, numerous people will still contract the infection. A minority of them will end up developing pneumonia, acute respiratory distress syndrome, and require ventilation.
Covid-19 patients show significantly high levels of proinflammatory cytokines (ICs) —proteins involved in lung inflammation that are overexpressed by a dysregulated immune response. A positive correlation has been found between the disease severity and the amount of cytokines present in the patients’ plasma. This “cytokine storm” eventually leads to fluid build-up in the lungs and multiple-organ failure by tissue damage. Targeting these proteins and their regulatory pathways (such as JAK/STAT) might be beneficial for attenuating the levels of immune dysfunction. One of these cytokines has been a subject of interest because of its involvement in many other inflammatory diseases, and previous work identified a small library of compounds to inhibit this protein.
Small molecule inhibitors (SMIs) can cause a conformational change in their target such that the protein is made unable to bind to its membrane receptor or do its job. Among this library, SMI10 has received several rounds of structural optimization to improve its binding to the IC and reduce the inflammatory pathway it induces. An amide functional group at the 2 position of the SMI’s furan core has been identified as a promising structural trait for making the compound a successful inhibitor. Further optimization on other areas of the small molecule is needed to achieve an IC-SMI dissociation constant lower than 1 μM and very low levels of pSTAT3 expression. These properties would make the SMI a candidate drug for treating the disastrous immune response caused by inflammatory diseases and possibly for mitigating the inflammation associated with a SARS-CoV-2 infection.
Feci, Andrea; Winkler, Emily; Tuccinardi, Joseph; Coughlin, Grace; Wolf, Cody; McGrath, Cooper; King, Matthew; Warner, Lisa R.; Jorcyk, Cheryl; and Warner, Don L., "Development of Small Molecules to Mitigate the SARS-CoV-2 Cytokine Storm" (2021). 2021 Undergraduate Research Showcase. 158.