Non‐Immunosuppressive Cyclophilin Inhibitors

Abstract

Cyclophilins, enzymes with peptidyl-prolyl cis/trans isomerase activity, are relevant to a large variety of biological processes. The most abundant member of this enzyme family, cyclophilin A, is the cellular receptor of the immunosuppressive drug cyclosporine A (CsA). As a consequence of the pathophysiological role of cyclophilins, particularly in viral infections, there is a broad interest in cyclophilin inhibition devoid of immunosuppressive activity. This Review first gives an introduction into the physiological and pathophysiological roles of cyclophilins. The presentation of non-immunosuppressive cyclophilin inhibitors will commence with drugs based on chemical modifications of CsA. The naturally occurring macrocyclic sanglifehrins have become other lead structures for cyclophilin-inhibiting drugs. Finally, de novo designed compounds, whose structures are not derived from or inspired by natural products, will be presented. Relevant synthetic concepts will be discussed, but the focus will also be on biochemical studies, structure-activity relationships, and clinical studies.

Effect of a High‐Fat Meal on Single‐Dose Rencofilstat (CRV431) Oral Bioavailability in Healthy Human Subjects

“…Additionally, modifications at position 3 may affect both calcineurin and Cyp binding directly or via conformational changes. The review by Schiene‐Fischer et al thoroughly explores the medicinal chemistry and synthesis of non‐immunosuppressive Cyp inhibitors 2 . Both this paper and work by Li et al 4 discuss alternative semisynthetic pathways to produce RCF.…”

“…To date, there are 17 known Cyp isoforms in humans, with well‐documented roles in many physiologic and pathophysiologic processes. RCF prevents collagen synthesis via Cyp B inhibition, with concomitant anti‐inflammatory and mitochondrial transition pore effects via Cyp A and Cyp D inhibition, respectively 1,2 . Preclinical chronic liver disease models demonstrated decreases in both fibrosis and tumor development by treatment with RCF.…”

“…The review by Schiene-Fischer et al thoroughly explores the medicinal chemistry and synthesis of non-immunosuppressive Cyp inhibitors. 2 Both this paper and work by Li et al 4 discuss alternative semisynthetic pathways to produce RCF. However, these methods do not describe the current proprietary method used for the synthesis of RCF for phase 2b and upcoming phase 3 trials.…”

“…RCF prevents collagen synthesis via Cyp B inhibition, with concomitant anti-inflammatory and mitochondrial transition pore effects via Cyp A and Cyp D inhibition, respectively. 1,2 Preclinical chronic liver disease models demonstrated decreases in both fibrosis and tumor development by treatment with RCF. In these models, RCF was found to inhibit Cyp A, B, D, and G with half maximal inhibitory concentration values of 2.5, 3.1, 2.8, and 7.3 nM, respectively.…”

Synthetic PROTACs based on a depsipeptide macrocycle selectively degrade cyclophilin A and inhibit HIV-1

“…The classical cyclophilin inhibitor CsA is not an effective antiviral due to potent immunosuppressive activity mediated via inhibition of the T cell phosphatase calcineurin 27 . Well-characterised, non-immunosuppressive variants of CsA have been developed, including NIM811, alisporivir (DEB025), SCY635 and CRV431 (CPI-431-32), all with considerable efficacy against HIV-1 and HCV replication 28,29 . However, alisporivir, the most promising, only had limited clinical efficacy against HIV-1 in HIV-1/HCV co-infected patients 30 and toxicity issues halted HCV trials in 2012 31 .…”