From chemical tools to clinical medicines: nonimmunosuppressive cyclophilin inhibitors derived from the cyclosporin and sanglifehrin scaffolds.

The cyclophilins are widely expressed enzymes that catalyze the interconversion of the cis and trans peptide bonds of prolines. The immunosuppressive natural products cyclosporine A and sanglifehrin A inhibit the enzymatic activity of the cyclophilins. Chemical modification of both the cyclosporine and sanglifehrin scaffolds has produced many analogues that inhibit cyclophilins in vitro but have reduced immunosuppressive properties. Three nonimmunosuppressive cyclophilin inhibitors (alisporivir, SCY-635, and NIM811) have demonstrated clinical efficacy for the treatment of hepatitis C infection. Additional candidates are in various stages of preclinical development for the treatment of hepatitis C or myocardial reperfusion injury. Recent publications suggest that cyclophilin inhibitors may have utility for the treatment of diverse viral infections, inflammatory indications, and cancer. In this review, we document the structure-activity relationships of the nonimmunosuppressive cyclosporins and sanglifehrins in clinical and preclinical development. Aspects of the pharmacokinetic behavior and chemical biology of these drug candidates are also described.

[1]  H. Wortelboer,et al.  Interaction of immunosuppressive drugs with human organic anion transporter (OAT) 1 and OAT3, and multidrug resistance-associated protein (MRP) 2 and MRP4. , 2013, Translational research : the journal of laboratory and clinical medicine.

[2]  J. Simon,et al.  Anti-inflammatory effects of extracellular cyclosporins are exclusively mediated by CD147. , 2013, Journal of medicinal chemistry.

[3]  Emily M. Lee,et al.  Cyclophilins as Modulators of Viral Replication , 2013, Viruses.

[4]  M. Peel,et al.  CHAPTER 11:Optimization of Cyclophilin Inhibitors for Use in Antiviral Therapy , 2013 .

[5]  M. Peel,et al.  Cyclophilin inhibitors as antiviral agents , 2013, Bioorganic & Medicinal Chemistry Letters.

[6]  R. Lokey,et al.  Form and Function in Cyclic Peptide Natural Products: A Pharmacokinetic Perspective , 2013 .

[7]  Matthias Rarey,et al.  Torsion angle preferences in druglike chemical space: a comprehensive guide. , 2013, Journal of medicinal chemistry.

[8]  H. Suga,et al.  Technologies for the Synthesis of mRNA-Encoding Libraries and Discovery of Bioactive Natural Product-Inspired Non-Traditional Macrocyclic Peptides , 2013, Molecules.

[9]  P. Gallay,et al.  Profile of alisporivir and its potential in the treatment of hepatitis C , 2013, Drug design, development and therapy.

[10]  T. Baumert,et al.  Host-targeting agents for prevention and treatment of chronic hepatitis C - perspectives and challenges. , 2013, Journal of hepatology.

[11]  J. Molkentin,et al.  Physiologic functions of cyclophilin D and the mitochondrial permeability transition pore. , 2013, Circulation journal : official journal of the Japanese Circulation Society.

[12]  J. Hiscott,et al.  HCV NS5A and IRF9 compete for CypA binding. , 2013, Journal of hepatology.

[13]  P. Gallay,et al.  Cyclophilin Inhibitors: An Emerging Class of Therapeutics for the Treatment of Chronic Hepatitis C Infection , 2012, Viruses.

[14]  Teresa A. Foster,et al.  Sangamides, a new class of cyclophilin-inhibiting host-targeted antivirals for treatment of HCV infection , 2012 .

[15]  M. Gregory,et al.  Multiple Mutations in Hepatitis C Virus NS5A Domain II Are Required To Confer a Significant Level of Resistance to Alisporivir , 2012, Antimicrobial Agents and Chemotherapy.

[16]  A. Sluder,et al.  The cyclophilin inhibitor SCY-635 suppresses viral replication and induces endogenous interferons in patients with chronic HCV genotype 1 infection. , 2012, Journal of hepatology.

[17]  P. Gallay,et al.  Cyclophilin involvement in the replication of hepatitis C virus and other viruses , 2012, Biological chemistry.

[18]  R. Gill,et al.  The Role of Cyclosporine in the Treatment of Myocardial Reperfusion Injury , 2012, Shock.

[19]  R. Flisiak,et al.  Update on alisporivir in treatment of viral hepatitis C , 2012, Expert opinion on investigational drugs.

[20]  T. Horie,et al.  Bile salt export pump inhibitors are associated with bile acid-dependent drug-induced toxicity in sandwich-cultured hepatocytes. , 2011, Biochemical and biophysical research communications.

[21]  F. Xue,et al.  Extracellular cyclophilin A may be a potential target to protect against myocardial reperfusion injury. , 2011, Medical hypotheses.

[22]  P. Sullivan,et al.  Post-injury administration of the mitochondrial permeability transition pore inhibitor, NIM811, is neuroprotective and improves cognition after traumatic brain injury in rats. , 2011, Journal of neurotrauma.

[23]  Richard Svensson,et al.  In Vitro and In Silico Strategies to Identify OATP1B1 Inhibitors and Predict Clinical Drug–Drug Interactions , 2011, Pharmaceutical Research.

[24]  Alexander Alex,et al.  Intramolecular hydrogen bonding to improve membrane permeability and absorption in beyond rule of five chemical space , 2011 .

[25]  Kai Lin.  Discovery of Cyclophilin Inhibitor NIM811 as a Novel Therapeutic Agent for HCV , 2011 .

[26]  M. Bukrinsky,et al.  Blocking cyclophilins in the chronic phase of asthma reduces the persistence of leukocytes and disease reactivation. , 2011, American journal of respiratory cell and molecular biology.

[27]  H. Hackstein,et al.  The Cyclophilin-Binding Agent Sanglifehrin A Is a Dendritic Cell Chemokine and Migration Inhibitor , 2011, PloS one.

[28]  Teresa A. Foster,et al.  Preclinical Characterization of Naturally Occurring Polyketide Cyclophilin Inhibitors from the Sanglifehrin Family , 2011, Antimicrobial Agents and Chemotherapy.

[29]  J. Jia,et al.  N‐methyl‐4‐isoleucine cyclosporine attenuates CCl4‐induced liver fibrosis in rats by interacting with cyclophilin B and D , 2011, Journal of gastroenterology and hepatology.

[30]  J. Praestgaard,et al.  Safety, pharmacokinetics, and antiviral activity of the cyclophilin inhibitor NIM811 alone or in combination with pegylated interferon in HCV-infected patients receiving 14 days of therapy. , 2011, Antiviral research.

[31]  Hasibur Rehman,et al.  NIM811 Prevents Mitochondrial Dysfunction, Attenuates Liver Injury, and Stimulates Liver Regeneration After Massive Hepatectomy , 2010, Transplantation.

[32]  M. Peel,et al.  Synthesis and biological evaluation of [D-lysine]8cyclosporin A analogs as potential anti-HCV agents. , 2010, Bioorganic & medicinal chemistry letters.

[33]  J. Molkentin,et al.  Debio-025 is more effective than prednisone in reducing muscular pathology in mdx mice , 2010, Neuromuscular Disorders.

[34]  G. Lippens,et al.  DEB025 (Alisporivir) Inhibits Hepatitis C Virus Replication by Preventing a Cyclophilin A Induced Cis-Trans Isomerisation in Domain II of NS5A , 2010, PloS one.

[35]  C. Bloomfield,et al.  P-glycoprotein inhibition using valspodar (PSC-833) does not improve outcomes for patients younger than age 60 years with newly diagnosed acute myeloid leukemia: Cancer and Leukemia Group B study 19808. , 2010, Blood.

[36]  A. Åsberg,et al.  Cyclosporine A, but Not Tacrolimus, Shows Relevant Inhibition of Organic Anion-Transporting Protein 1B1-Mediated Transport of Atorvastatin , 2010, Drug Metabolism and Disposition.

[37]  Jinhwa Lee,et al.  Current implications of cyclophilins in human cancers , 2010, Journal of experimental & clinical cancer research : CR.

[38]  A. Galat,et al.  Molecular aspects of cyclophilins mediating therapeutic actions of their ligands , 2010, Cellular and Molecular Life Sciences.

[39]  E. Eisenmesser,et al.  Structural and Biochemical Characterization of the Human Cyclophilin Family of Peptidyl-Prolyl Isomerases , 2010, PLoS biology.

[40]  E. Eisenmesser,et al.  Cyclophilin–CD147 interactions: a new target for anti-inflammatory therapeutics , 2010, Clinical and experimental immunology.

[41]  Traci Galbaugh,et al.  Cyclophilin B as a co-regulator of prolactin-induced gene expression and function in breast cancer cells. , 2010, Journal of molecular endocrinology.

[42]  X. Puyang,et al.  Mechanism of Resistance of Hepatitis C Virus Replicons to Structurally Distinct Cyclophilin Inhibitors , 2010, Antimicrobial Agents and Chemotherapy.

[43]  S. Kuroda,et al.  Pretreatment with the ciclosporin derivative NIM811 reduces delayed neuronal death in the hippocampus after transient forebrain ischaemia , 2010, The Journal of pharmacy and pharmacology.

[44]  M. Niemi,et al.  Membrane transporters in drug development , 2010, Nature Reviews Drug Discovery.

[45]  T. Bouwmeester,et al.  Multiple cyclophilins involved in different cellular pathways mediate HCV replication. , 2010, Virology.

[46]  H. R. Bergen,et al.  Severe Osteogenesis Imperfecta in Cyclophilin B–Deficient Mice , 2009, PLoS genetics.

[47]  G. Fischer,et al.  SCY-635, a Novel Nonimmunosuppressive Analog of Cyclosporine That Exhibits Potent Inhibition of Hepatitis C Virus RNA Replication In Vitro , 2009, Antimicrobial Agents and Chemotherapy.

[48]  Y. Sugiyama,et al.  Long-Lasting Inhibition of the Transporter-Mediated Hepatic Uptake of Sulfobromophthalein by Cyclosporin A in Rats , 2009, Drug Metabolism and Disposition.

[49]  Hasibur Rehman,et al.  NIM811 (N-Methyl-4-isoleucine Cyclosporine), a Mitochondrial Permeability Transition Inhibitor, Attenuates Cholestatic Liver Injury but Not Fibrosis in Mice , 2008, Journal of Pharmacology and Experimental Therapeutics.

[50]  E. Hall,et al.  Attenuation of acute mitochondrial dysfunction after traumatic brain injury in mice by NIM811, a non-immunosuppressive cyclosporin A analog , 2008, Experimental Neurology.

[51]  L. Pettigrew,et al.  Protective effects of NIM811 in transient focal cerebral ischemia suggest involvement of the mitochondrial permeability transition. , 2007, Journal of neurotrauma.

[52]  T. Theruvath,et al.  NIM811, a Mitochondrial Permeability Transition Inhibitor, Prevents Mitochondrial Depolarization in Small‐for‐Size Rat Liver Grafts , 2007, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[53]  P. Bernardi,et al.  The mitochondrial permeability transition pore and its involvement in cell death and in disease pathogenesis , 2007, Apoptosis.

[54]  K. Shimotohno,et al.  Evaluation of the anti-hepatitis C virus effects of cyclophilin inhibitors, cyclosporin A, and NIM811. , 2006, Biochemical and biophysical research communications.

[55]  E. De Clercq,et al.  The non‐immunosuppressive cyclosporin DEBIO‐025 is a potent inhibitor of hepatitis C virus replication in vitro , 2006, Hepatology.

[56]  M. Bukrinsky,et al.  Dealing with the family: CD147 interactions with cyclophilins , 2006, Immunology.

[57]  P. Sonneveld,et al.  Phase III study of PSC‐833 (valspodar) in combination with vincristine, doxorubicin, and dexamethasone (valspodar/VAD) versus VAD alone in patients with recurring or refractory multiple myeloma (E1A95) , 2006, Cancer.

[58]  C. Härtel,et al.  Immunosuppressive Activity of the Immunophilin‐binding Drug Sanglifehrin A in Human Whole Blood: Potent Inhibition of Interleukin‐6 Produced by Lymphocytes and Monocytes , 2006, Scandinavian journal of immunology.

[59]  R. Ptak,et al.  Naturally Occurring Capsid Substitutions Render HIV-1 Cyclophilin A Independent in Human Cells and TRIM-cyclophilin-resistant in Owl Monkey Cells* , 2005, Journal of Biological Chemistry.

[60]  M. Bukrinsky,et al.  Cell Surface Expression of CD147/EMMPRIN Is Regulated by Cyclophilin 60* , 2005, Journal of Biological Chemistry.

[61]  R. Sedrani,et al.  Structure of Human Cyclophilin A in Complex with the Novel Immunosuppressant Sanglifehrin A at 1.6 Å Resolution* , 2005, Journal of Biological Chemistry.

[62]  A. Ruiz,et al.  In vitro anti-parasitic activity of Cyclosporin A analogs on Trypanosoma cruzi. , 2004, Bioorganic & medicinal chemistry letters.

[63]  A. Galat.  Function‐dependent clustering of orthologues and paralogues of cyclophilins , 2004, Proteins.

[64]  A. Bousseau,et al.  Synthesis of non-immunosuppressive cyclophilin-Binding cyclosporin A derivatives as potential anti-HIV-1 drugs. , 2003, Bioorganic & medicinal chemistry letters.

[65]  Francesco Senia,et al.  Sanglifehrin-cyclophilin interaction: degradation work, synthetic macrocyclic analogues, X-ray crystal structure, and binding data. , 2003, Journal of the American Chemical Society.

[66]  H. Herscovitz,et al.  Nascent Lipidated Apolipoprotein B Is Transported to the Golgi as an Incompletely Folded Intermediate as Probed by Its Association with Network of Endoplasmic Reticulum Molecular Chaperones, GRP94, ERp72, BiP, Calreticulin, and Cyclophilin B* , 2003, The Journal of Biological Chemistry.

[67]  S. Harrison,et al.  Crystal structure of human calcineurin complexed with cyclosporin A and human cyclophilin , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[68]  R. Traber,et al.  Cyclosporins: structure-activity relationships for the inhibition of the human MDR1 P-glycoprotein ABC transporter. , 2002, Journal of medicinal chemistry.

[69]  John J Lemasters,et al.  Inhibition of the mitochondrial permeability transition by the nonimmunosuppressive cyclosporin derivative NIM811. , 2002, Molecular pharmacology.

[70]  F. Akhlaghi,et al.  Distribution of Cyclosporin in Organ Transplant Recipients , 2002, Clinical pharmacokinetics.

[71]  M. Zurini,et al.  Sanglifehrin A, a Novel Cyclophilin-Binding Compound Showing Immunosuppressive Activity with a New Mechanism of Action , 2001, The Journal of Immunology.

[72]  A. Pletscher,et al.  The controversial early history of cyclosporin. , 2001, Swiss medical weekly.

[73]  M. Mutter,et al.  Synthetic routes to NEtXaa4-cyclosporin A derivatives as potential anti-HIV I drugs , 2000 .

[74]  K. Memmert,et al.  Sanglifehrins A, B, C and D, novel cyclophilin-binding compounds isolated from Streptomyces sp. A92-308110. I. Taxonomy, fermentation, isolation and biological activity. , 1999, The Journal of antibiotics.

[75]  P. Taylor,et al.  Conformational differences of an immunosuppressant peptolide in a single crystal and in a crystal complex with human cyclophilin A. , 1998, Journal of molecular biology.

[76]  S. Ko,et al.  Solid‐Phase Total Synthesis of Cyclosporine Analogues , 1997 .

[77]  H. Husi,et al.  Structures of cyclophilin-ligand complexes. , 1997, Progress in biophysics and molecular biology.

[78]  J. Kallen,et al.  Conformational control of cyclosporin through substitution of the N-5 position. A new class of cyclosporin antagonists. , 1997, Bioorganic & medicinal chemistry.

[79]  R. Traber,et al.  Anti HIV-1 activity of a hydrophilic cyclosporin derivative with improved binding affinity to cyclophilin A , 1996 .

[80]  A. Burgess,et al.  Modeling conformational changes in cyclosporin A , 1995, Protein science : a publication of the Protein Society.

[81]  P. Hiestand,et al.  Preparation and in vitro activities of ethers of [D-serine]8-cyclosporin. , 1995, Journal of medicinal chemistry.

[82]  B. Rosenwirth,et al.  Mode of action of SDZ NIM 811, a nonimmunosuppressive cyclosporin A analog with activity against human immunodeficiency virus (HIV) type 1: interference with HIV protein-cyclophilin A interactions , 1995, Journal of virology.

[83]  D. Altschuh,et al.  Interaction of cyclosporin A and two cyclosporin analogs with cyclophilin: relationship between structure and binding. , 1994, Journal of chromatography. B, Biomedical applications.

[84]  V. Mikol,et al.  Improved binding affinity for cyclophilin A by a cyclosporin derivative singly modified at its effector domain. , 1994, Journal of medicinal chemistry.

[85]  J. France,et al.  The 3D structure of a cyclosporin analogue in water is nearly identical to the cyclophilin‐bound cyclosporin conformation , 1994, FEBS letters.

[86]  C. Papageorgiou,et al.  Calcineurin has a very tight-binding pocket for the side chain of residue 4 of cyclosporin , 1994 .

[87]  M. Okuhara,et al.  FR901459, a novel immunosuppressant isolated from Stachybotrys chartarum No. 19392. Taxonomy of the producing organism, fermentation, isolation, physico-chemical properties and biological activities. , 1993, The Journal of antibiotics.

[88]  M. Walkinshaw,et al.  X-ray structure of a monomeric cyclophilin A-cyclosporin A crystal complex at 2.1 A resolution. , 1993, Journal of molecular biology.

[89]  D. Seebach,et al.  Modification of Cyclosporin A (CS): Generation of an enolate at the sarcosine residue and reactions with electrophiles , 1993 .

[90]  M. Walkinshaw,et al.  X-ray structure of a decameric cyclophilin-cyclosporin crystal complex , 1993, Nature.

[91]  Y. Thériault,et al.  Solution structure of the cyclosporin A/cyclophilin complex by NMR , 1993, Nature.

[92]  S. Schreiber.  Immunophilin-sensitive protein phosphatase action in cell signaling pathways , 1992, Cell.

[93]  S. Schreiber,et al.  The conformation of cyclosporin a bound to cyclophilin is altered (once again) following binding to calcineurin: an analysis of receptor-ligand-receptor interactions , 1992 .

[94]  U. Christians,et al.  The synergistic immunosuppressive potential of cyclosporin metabolite combinations. , 1992, International journal of immunopharmacology.

[95]  Jun O. Liu,et al.  Inhibition of T cell signaling by immunophilin-ligand complexes correlates with loss of calcineurin phosphatase activity. , 1992, Biochemistry.

[96]  S. Schreiber,et al.  The mechanism of action of cyclosporin A and FK506. , 1992, Immunology today.

[97]  D. Geyl,et al.  In vitro biosynthesis of [Thr2,Leu5,D-Hiv8,Leu10]-cyclosporin, a cyclosporin-related peptolide, with immunosuppressive activity by a multienzyme polypeptide. , 1991, The Journal of biological chemistry.

[98]  N. Sigal,et al.  Is cyclophilin involved in the immunosuppressive and nephrotoxic mechanism of action of cyclosporin A? , 1991, The Journal of experimental medicine.

[99]  D. Seebach,et al.  C-alkylation of peptides through polylithiated and LiCl-solvated derivatives containing sarcosine Li-enolate units , 1991 .

[100]  B. Ryffel,et al.  Pharmacology of cyclosporine (sandimmune). I. Introduction. , 1990, Pharmacological reviews.

[101]  T. Kiefhaber,et al.  Cyclophilin and peptidyl-prolyl cis-trans isomerase are probably identical proteins , 1989, Nature.

[102]  T. Hayano,et al.  Peptidyl-prolyl cis-trans isomerase is the cyclosporin A-binding protein cyclophilin , 1989, Nature.

[103]  T. Kawai,et al.  Effect of cyclosporine on proliferation of non-A, non-B hepatitis virus. , 1988, Transplantation proceedings.

[104]  H. Loosli,et al.  Neue Cyclosporine aus Tolypocladium inflatum. Die Cyclosporine K–Z† , 1987 .

[105]  M. Schreier,et al.  Cyclophilin binds to the region of cyclosporine involved in its immunosuppressive activity , 1987, European journal of immunology.

[106]  D. Speicher,et al.  Isolation and amino acid sequence of cyclophilin. , 1986, The Journal of biological chemistry.

[107]  R Wenger,et al.  Cyclosporine and analogues: structural requirements for immunosuppressive activity. , 1985, Transplantation proceedings.

[108]  M. Schreier,et al.  Cyclosporine: Chemistry, Structure-Activity Relationships and Mode of Action , 1986 .

[109]  P. Colombani,et al.  Cyclosporin A binding to calmodulin: a possible site of action on T lymphocytes. , 1985, Science.

[110]  R. Sawchuk,et al.  The pharmacokinetics of cyclosporine. II. Blood plasma distribution and binding studies. , 1985, Drug metabolism and disposition: the biological fate of chemicals.

[111]  D. Speicher,et al.  Cyclophilin: a specific cytosolic binding protein for cyclosporin A. , 1984, Science.

[112]  R. Wenger.  Synthesis of cyclosporine. Total syntheses of ‘cyclosporin A’ and ‘cyclosporin H’, two fungal metabolites isolated from the species Tolypocladium inflatum GAMS , 1984 .