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

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2023 · $443,750

## Abstract

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 invest...

## Key facts

- **NIH application ID:** 10594993
- **Project number:** 5R01AI143931-04
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** PHILIPPE ANDRE GALLAY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $443,750
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10594993

## Citation

> US National Institutes of Health, RePORTER application 10594993, Non-immunosuppressive Sanglifehrin Analogs as Therapeutic Agents for Viral Hepatitis-induced Liver Damage Development (5R01AI143931-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10594993. Licensed CC0.

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