Cyclophilin Inhibitors in Coronavirus Therapeutics

Cyclophilin inhibitors have emerged as a promising host‐targeted strategy against coronaviruses, leveraging the dependence of viral replication on cellular cyclophilins. These prolyl isomerases facilitate proper folding of viral proteins and modulate immune signalling pathways, including calcineurin‐mediated activation. By binding to cyclophilins, compounds such as cyclosporin A (CsA) and non‐immunosuppressive analogues can simultaneously inhibit viral genome replication and temper excessive inflammatory responses, notably the cytokine storm associated with severe disease. Formulations under investigation range from systemic administration to inhalable dry powders engineered for deep lung delivery. Preclinical studies demonstrate broad‐spectrum activity across multiple coronavirus genera, and early clinical trials have begun to assess safety and efficacy in preventing post‐infectious pulmonary complications. This host‐directed approach may retain activity against emerging variants and offers potential for combination with direct‐acting antivirals to achieve synergistic suppression of viral replication and inflammation.

Research from Nature Portfolio

A recent pilot randomised clinical trial evaluated the addition of CsA to standard of care in patients hospitalised with COVID-19 pneumonia to prevent medium-term interstitial lung disease. Thirty-three participants were allocated to receive either CsA plus standard therapy or standard therapy alone, with outcomes assessed at three months post-diagnosis. While no statistically significant reduction in the development of interstitial lung disease or need for invasive mechanical ventilation was observed, there was a trend towards improved composite response rates irrespective of ventilation status in the CsA group. The safety profile was comparable between arms, underscoring the feasibility of further larger-scale trials to determine the role of CsA in mitigating post-COVID pulmonary fibrosis.

Cyclophilin Inhibitors in Coronavirus Therapeutics publication trend

The graph below shows the total number of articles in cyclophilin inhibitors in coronavirus therapeutics across all publications each year (not limited to Nature Index journals).

Technical terms

Cyclophilin: A cellular enzyme that catalyses proline isomerisation, important for protein folding and viral replication.

Cyclophilin inhibitor: A molecule that binds to cyclophilins, preventing their enzymatic function and thereby impeding virus life cycles.

Cyclosporin A (CsA): An immunosuppressive drug repurposed for its ability to inhibit cyclophilins and modulate immune responses.

Calcineurin: A phosphatase activated by cyclophilin complexes, central to T-cell activation and cytokine production.

Non-structural protein 1 (Nsp1): A viral protein that interacts with host factors to suppress immune responses and enhance coronavirus replication.

Pan-coronavirus inhibitor: An agent effective against multiple coronavirus species by targeting conserved host or viral mechanisms.

Cytokine storm: An excessive immune reaction characterised by high levels of pro-inflammatory cytokines, such as interleukin-6, contributing to tissue damage.

References

1. An Enhanced Dissolving Cyclosporin-A Inhalable Powder Efficiently Reduces SARS-CoV-2 Infection In Vitro. Pharmaceutics (2023).
2. Cyclosporine A in hospitalized COVID-19 pneumonia patients to prevent the development of interstitial lung disease: a pilot randomized clinical trial. Scientific Reports (2024).
3. The SARS-Coronavirus-Host Interactome: Identification of Cyclophilins as Target for Pan-Coronavirus Inhibitors. PLOS Pathogens (2011).
4. Remdesivir and Cyclosporine Synergistically Inhibit the Human Coronaviruses OC43 and SARS-CoV-2. Frontiers in Pharmacology (2021).