What Is Alisporivir? Definition and What Research Reports

Definition

Alisporivir — also written in the literature as Debio 025 or DEB025 — is a synthetic analogue of cyclosporin A that was characterised as a cyclosporin derivative selectively inhibiting cyclophilin and studied for hepatitis C virus (HCV) infection (PMID 20112171). Unlike its parent molecule, it is described as non-immunosuppressive: chemical modification of the cyclosporin scaffold was intended to retain cyclophilin binding while removing calcineurin-mediated immune suppression. Because cyclosporin A is a cyclic undecapeptide (an eleven-residue macrocyclic peptide of fungal origin), alisporivir sits in the same structural family, which is why the term appears in peptide and macrocycle reference material rather than only in small-molecule antiviral literature.

What Class of Molecule It Is

Alisporivir is a semi-synthetic macrocyclic peptide. Its ring is built from amino acid residues, several of them N-methylated and non-canonical, which is characteristic of fungal cyclic peptides and contributes to the metabolic stability and membrane behaviour that distinguish such macrocycles from linear peptides. A 2022 biophysical comparison examined the structural properties of cyclosporin A and alisporivir alongside their effects on mitochondrial bioenergetics and membrane behaviour, reporting that the two analogues differ in how they interact with lipid membranes despite their shared scaffold (PMID 35643328).

Its molecular target is the cyclophilin family — peptidyl-prolyl isomerases found in the cytosol and mitochondria. Cyclophilin A is described in review literature as a host factor co-opted by HCV during replication, which made it an attractive target for a host-targeting antiviral rather than a direct-acting one (PMID 23440335). Mitochondrial cyclophilin D, a separate family member, is a regulator of the mitochondrial permeability transition (MPT) pore, which explains the second, entirely non-viral research literature described below.

How the Term Is Used in Peptide Research

Three usages dominate:

• As a host-targeting antiviral candidate. Reviews positioned alisporivir as an agent acting on a host protein rather than a viral enzyme, a mechanism proposed to make resistance emergence less straightforward than with direct-acting antivirals (PMID 23440335).
• As a cyclophilin-inhibitor tool compound. In cell and animal studies it is used to ask what happens when cyclophilin function — particularly cyclophilin D at the MPT pore — is blocked.
• As a case study in macrocyclic peptide design. It is frequently cited as an example of modifying a natural cyclic peptide to separate one activity (cyclophilin binding) from another (immunosuppression).

What the Published Literature Reports

Hepatitis C

HCV is the largest body of work. A 2013 profile review described alisporivir's mechanism and its potential in the treatment of hepatitis C, framing cyclophilin inhibition as an approach distinct from direct-acting antivirals (PMID 23440335), and a 2010 review in Current Opinion in Investigational Drugs summarised early development of the compound for HCV infection (PMID 20112171). A later 2019 review in Expert Opinion on Pharmacotherapy assessed the efficacy and safety of alisporivir for the treatment of hepatitis C infection as that clinical programme was evaluated (PMID 30576256).

Combination work has also been published: researchers reported that alisporivir plus an NS5A inhibitor produced additive to synergistic anti-HCV activity in vitro without detectable cross-resistance between the two mechanisms (PMID 24687498).

Hepatitis B

A 2015 Gastroenterology study reported that alisporivir inhibition of hepatocyte cyclophilins reduced hepatitis B virus replication and hepatitis B surface antigen production in experimental systems (PMID 25305505).

Other pathogens

A 2020 report in Antimicrobial Agents and Chemotherapy described inhibition of SARS-CoV-2 infection by the cyclophilin inhibitor alisporivir (Debio 025) in cell culture (PMID 32376613). Separately, a 2022 study examined repurposing the anti-hepatitis C drug alisporivir against artemisinin-resistant malaria parasites (PMID 36374050). Both were preclinical, laboratory-stage investigations.

Immune effects

Because alisporivir was designed not to suppress immunity, its immune profile has itself been studied. A 2016 Journal of Hepatology study reported that the cyclophilin inhibitor alisporivir stimulated antigen presentation, thereby promoting antigen-specific CD8+ T cell activation (PMID 26921685).

Mitochondrial permeability transition

A distinct line of animal research uses alisporivir as an MPT pore inhibitor. In dystrophin-deficient mice, one study examined its effect on calcium ion transport and mitophagy in skeletal muscle and heart mitochondria (PMID 35501648). In diabetes models, researchers reported that alisporivir treatment alleviated mitochondrial dysfunction in the skeletal muscles of C57BL/6NCrl mice with high-fat-diet/streptozotocin-induced diabetes mellitus (PMID 34502433), and a companion study assessed the effect of the MPT pore inhibitor alisporivir on the development of mitochondrial dysfunction in heart tissue of diabetic mice (PMID 34571715). These were animal and isolated-mitochondria experiments; the published dosing details of those protocols are outside the scope of this definitional entry and are not reproduced here.

Research Areas at a Glance

Safety and Tolerability: What Studies Report

Safety data for alisporivir come from its hepatitis C development programme rather than from any approved product. The 2019 Expert Opinion on Pharmacotherapy review was written specifically to appraise the efficacy and safety of alisporivir for hepatitis C infection, and readers seeking event-level detail are directed to that primary source (PMID 30576256); the 2013 profile review likewise discussed the compound's clinical profile in HCV (PMID 23440335). This glossary entry does not summarise specific adverse events, incidence rates or dosing from those programmes, because such figures should be read in their original clinical context.

Regulatory and Practical Status

Alisporivir has not been approved as a medicine by the FDA or EMA. In the literature it appears as an investigational compound and, in laboratory catalogues, as a research-use-only material for in vitro and animal work. Direct-acting antiviral regimens became the standard of care for hepatitis C, and reviews of alisporivir are best read as documentation of an alternative, host-targeting strategy rather than of a currently marketed therapy (PMID 30576256).

Limitations of the Evidence

• Much of the non-viral work — the mitochondrial and muscle studies — was carried out in mice and isolated mitochondria, and animal findings do not transfer directly to humans.
• The SARS-CoV-2 and malaria findings were cell-based or preclinical; neither review-level nor outcome data in people were presented in those reports.
• Clinical evidence is concentrated in hepatitis C, a field that has since changed substantially.

This page is for educational purposes only and is not medical advice; consult a licensed physician before making any health decision. It describes what published studies reported about alisporivir and does not recommend, endorse or describe any personal use of the compound.

References

• Profile of alisporivir and its potential in the treatment of hepatitis C (Drug Design, Development and Therapy, 2013)
• Alisporivir, a cyclosporin derivative that selectively inhibits cyclophilin, for the treatment of HCV infection (Current Opinion in Investigational Drugs, 2010)
• Efficacy and safety of alisporivir for the treatment of hepatitis C infection (Expert Opinion on Pharmacotherapy, 2019)
• The combination of alisporivir plus an NS5A inhibitor provides additive to synergistic anti-hepatitis C virus activity without detectable cross-resistance (Antimicrobial Agents and Chemotherapy, 2014)
• Alisporivir inhibition of hepatocyte cyclophilins reduces HBV replication and hepatitis B surface antigen production (Gastroenterology, 2015)
• Inhibition of SARS-CoV-2 Infection by the Cyclophilin Inhibitor Alisporivir (Debio 025) (Antimicrobial Agents and Chemotherapy, 2020)
• Targeting Artemisinin-Resistant Malaria by Repurposing the Anti-Hepatitis C Virus Drug Alisporivir (Antimicrobial Agents and Chemotherapy, 2022)
• The cyclophilin-inhibitor alisporivir stimulates antigen presentation thereby promoting antigen-specific CD8(+) T cell activation (Journal of Hepatology, 2016)
• Effect of Alisporivir on Calcium Ion Transport and Mitophagy in Skeletal Muscle and Heart Mitochondria in Dystrophin-Deficient Mice (Bulletin of Experimental Biology and Medicine, 2022)
• Alisporivir Treatment Alleviates Mitochondrial Dysfunction in the Skeletal Muscles of C57BL/6NCrl Mice with High-Fat Diet/Streptozotocin-Induced Diabetes Mellitus (International Journal of Molecular Sciences, 2021)
• Effect of the MPT Pore Inhibitor Alisporivir on the Development of Mitochondrial Dysfunction in the Heart Tissue of Diabetic Mice (Biology, 2021)
• Comparison of structural properties of cyclosporin A and its analogue alisporivir and their effects on mitochondrial bioenergetics and membrane behavior (BBA Biomembranes, 2022)