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Targeting the VHR phosphatase for the treatment of sepsis in COVID-19 patients

Award Number: R21AI160161
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/06/2021
PERIOD OF PERFORMANCE END DATE: 09/30/2023

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Targeting the VHR phosphatase for the treatment of sepsis in COVID-19 patients - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	2	5/15/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	2	3/29/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $243,750 )
2022	2022	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	2	7/1/2022	NON-COMPETING CONTINUATION	$0
2022	2022	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	2	3/25/2022	NON-COMPETING CONTINUATION	$243,750
														Subtotal = $243,750

Issue Date FY: 2021 ( Subtotal = $292,500 )
2021	2021	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	1	4/6/2021	NEW	$292,500
2021	2021	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	1	4/7/2021	NEW	$0
														Subtotal = $292,500

Grand Total All Awards = $536,250

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Targeting the VHR phosphatase for the treatment of sepsis in COVID-19 patients

Award Number: R21AI160161

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/06/2021

PERIOD OF PERFORMANCE END DATE: 09/30/2023

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