Saturday, April 20, 2024
4/20/2024
PROJECT SUMMARY Recent studies have demonstrated that severe or critically ill coronavirus disease 2019 (COVID-19) patients develop typical clinical manifestations of sepsis and septic shock, serious medical condition characterized by dysregulated systemic inflammation and excessive release of proinflammatory cytokines. The cytokine storm is followed by immunosuppression, ultimately leading to tissue damage, organ failure, and often death. Effective treatment options for sepsis and septic shock are limited, and the mortality rate is extremely high with up to 50% for sepsis and up to 80% for septic shock. The dual-specificity phosphatase 3 (DUSP3), also known as Vaccinia- H1-related phosphatase (VHR), is highly expressed in monocytes and macrophages and plays a critical role as a positive regulator of the innate immune response. Genetic deletion of VHR confers strong protection against endotoxin shock and polymicrobial septic shock. VHR-/- mice are resistant to inflammatory shock induced by lipopolysaccharides (LPS) and cecum ligation and puncture (CLP)-induced sepsis. This protection is associated with decreased systemic production of proinflammatory cytokines such as TNF and IL-6, which are elevated in COVID-19 patients. Based on these findings, inhibition of VHR with small molecule inhibitors may be beneficial for the treatment of sepsis and septic shock, which are responsible for the majority of COVID-19 deaths. Importantly, VHR knockout mice are healthy, fertile, and show no spontaneous phenotypic abnormalities, suggesting that specific drugs targeting VHR may have no deleterious side effects. We previously reported a VHR small molecule inhibitor, MLS-0437605, with good potency and selectivity. We propose to optimize this compound for in vivo studies in the CLP mouse model of septic shock. Success in generating a specific VHR inhibitor that protects mice from septic shock in the CLP model will prompt additional preclinical development towards a clinical candidate in future studies. To achieve these objectives, our aims are to 1) define the allosteric binding site in VHR targeted by MLS-0437605, and 2) to optimize the potency, selectivity, and drug-like properties of MLS-0437605, and to assess the efficacy of optimized compounds in cellular and in vivo models. This proposal leverages the expertise of an established and well-functioning team that has been collaborating on several phosphatase drug discovery projects in the past.
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