Tuesday, May 13, 2025 5/13/2025

Non-immunosuppressive Sanglifehrin Analogs as Therapeutic Agents for Viral Hepatitis-induced Liver Damage Development

Award Number: R01AI143931
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Non-immunosuppressive Sanglifehrin Analogs as Therapeutic Agents for Viral Hepatitis-induced Liver Damage Development - HCV and HBV represent the leading cause of hepatocellular carcinoma (HCC). The risk of HCC remains even after virus elimination. Thus, it is of the utmost importance to identify novel approaches to treat viral hepatitis- induced HCC. We identified a novel class of small compounds called sanglifehrin derivates (SfDer), which possess antiviral and anti-cellular activities critical for preventing viral hepatitis-induced HCC development. Recent findings highlight that our application is highly significant: i) HCC represents the fastest growing cause of cancer mortality; ii) Recent studies raised a red flag regarding unexpected higher rates of HCC recurrence following DAA treatment, indicating that viral hepatitis-associated HCC remains an unresolved and significant public health issue; iii) Patients with HCC are 8 times more likely to fail DAA treatment than patients without HCC; iv) The FDA confirmed the high risk of HBV reactivation after DAA therapy; and v) Besides sorafenib, which improves survival by only 2-3 months, >100 trials evaluating therapies for HCC failed to show survival advantages. Therefore, there is an urgent need for the identification of new combinations of drugs with distinct mechanisms of action (MoA) that concurrently inhibit HCV/HBV infections and viral hepatitis-induced HCC. We demonstrated that SfDer possess remarkable activities critical for the treatment of viral hepatitis infection and HCC: i) SfDer suppress HCV and HBV replication in vitro as well as in mice even when viral replication in implanted hepatocytes is robust; ii) SfDer are not cytotoxic even when used at high doses; iii) SfDer, but not another class of structurally distinct cyclophilin inhibitors (CypI) – cyclosporine A derivates (CsADer) – possess the unique property of stopping growth of hepatoma cells, but not that of hepatocytes; iv) SfDer inhibit in vitro and in vivo HCV and HBV replication in human hepatocytes, which are resistant to the SfDer-mediated cytostaticity, demonstrating authentic antiviral activities unrelated to their cytostatic activities; v) SfDer inhibit viral hepatitis-induced HCC; vi) SfDer inhibit HCC in a nonviral-induced HCC mouse model; and vii) SfDer modulate hepatic levels of cytokines during HCC development. Thus, SfDer represent novel attractive drugs to be part of therapies for HCV and HBV mono- and co-infections as well as viral hepatitis-induced HCC. In Aim 1, we will investigate SfDer efficacy at inhibiting viral hepatitis infection and HCC induction in mice. We will examine whether the inclusion of SfDer into DAA regimens improves their beneficial effect against viral hepatitis infection and HCC induction, whether HCV/HBV co-infection induces more severe HCC than mono- infection, and whether SfDer inhibit co-infection and co-infection-induced HCC. In Aim 2, we will investigate whether the newly identified cyclophilin A-HBx interactions, which are prevented by SfDer, are critical for HBV replication. In Aim 3, we will investigate the efficacy of SfDer at preventing nonviral-induced HCC. We also will investigate at a molecular level the MoA that allow SfDer to stop hepatoma cell growth (not hepatocytes) – a unique property that may contribute to their anti-HCC impact.


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 = $452,500 )
2024	2024	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	5	3/21/2024	NON-COMPETING CONTINUATION	$452,500
														Subtotal = $452,500

Issue Date FY: 2023 ( Subtotal = $443,750 )
2023	2023	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	4	3/29/2023	NON-COMPETING CONTINUATION	$443,750
														Subtotal = $443,750

Issue Date FY: 2022 ( Subtotal = $443,750 )
2022	2022	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	3	3/21/2022	NON-COMPETING CONTINUATION	$443,750
														Subtotal = $443,750

Issue Date FY: 2021 ( Subtotal = $443,750 )
2021	2021	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	2	3/18/2021	NON-COMPETING CONTINUATION	$443,750
														Subtotal = $443,750

Issue Date FY: 2020 ( Subtotal = $443,750 )
2020	2020	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	1	3/27/2020	NEW	$443,750
														Subtotal = $443,750

Grand Total All Awards = $2,227,500

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Non-immunosuppressive Sanglifehrin Analogs as Therapeutic Agents for Viral Hepatitis-induced Liver Damage Development

Award Number: R01AI143931

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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