Design and Synthesis of Conformationally Constrained Cyclophilin Inhibitors Showing a Cyclosporin‐A Phenotype in <i>C. elegans</i>

Dunsmore, Colin J.; Malone, Kirk J.; Bailey, Kevin; Wear, Martin A.; Florance, Hannah; Shirran, Sally L.; Barran, Perdita E.; Page, Antony P.; Walkinshaw, Malcolm D.; Turner, Nicholas J.

doi:10.1002/cbic.201000413

Cited by 9 publications

(5 citation statements)

References 39 publications

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“…Altogether, these results cast doubt as to the reality of the anti-cyclophilin properties of this class of molecules. Other families of compounds have been reported to inhibit cyclophilin activity in vitro , but they need to be externally validated and their potential as broad-spectrum antiviral compounds has not been evaluated 38 39 40 . These results emphasize the difficulty of developing efficacious small-molecule cyclophilin inhibitors unrelated to CsA or SfA and underline the originality and importance of our work.…”

Section: Discussionmentioning

confidence: 99%

Fragment-based discovery of a new family of non-peptidic small-molecule cyclophilin inhibitors with potent antiviral activities

et al. 2016

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Cyclophilins are peptidyl-prolyl cis/trans isomerases (PPIase) that catalyse the interconversion of the peptide bond at proline residues. Several cyclophilins play a pivotal role in the life cycle of a number of viruses. The existing cyclophilin inhibitors, all derived from cyclosporine A or sanglifehrin A, have disadvantages, including their size, potential for side effects unrelated to cyclophilin inhibition and drug–drug interactions, unclear antiviral spectrum and manufacturing issues. Here we use a fragment-based drug discovery approach using nucleic magnetic resonance, X-ray crystallography and structure-based compound optimization to generate a new family of non-peptidic, small-molecule cyclophilin inhibitors with potent in vitro PPIase inhibitory activity and antiviral activity against hepatitis C virus, human immunodeficiency virus and coronaviruses. This family of compounds has the potential for broad-spectrum, high-barrier-to-resistance treatment of viral infections.

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Section: Discussionmentioning

confidence: 99%

Fragment-based discovery of a new family of non-peptidic small-molecule cyclophilin inhibitors with potent antiviral activities

et al. 2016

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“…Recent studies revealed that large, hydrophobic peptides are often OATP inhibitors . To overcome these disadvantages, Gouichou et al focused on developing small molecule inhibitors. − Using a fragment-based drug design (FBDD) approach, in which over 34 409 fragments were screened to fit into the CypD binding pocket, they identified two lead fragments in the initial step . Superimposition of those fragments with the known structures of CsA ( 5 ) and SfA ( 40 ) suggested that a urea moiety could be used as a linker between the two fragments because of one hydrogen bond with Gln63 and two with Asn102 .…”

Section: Potential To Develop Inhibitors Of Bacterial Cyclophilinsmentioning

confidence: 99%

Targeting Protein Folding: A Novel Approach for the Treatment of Pathogenic Bacteria

et al. 2020

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Infectious diseases are a major cause of morbidity and mortality worldwide, exacerbated by increasing antibiotic resistance in many bacterial species. The development of drugs with new modes of action is essential. A leading strategy is antivirulence, with the aim to target bacterial proteins that are important in disease causation and progression but do not affect growth, resulting in reduced selective pressure for resistance. Immunophilins, a superfamily of peptidyl-prolyl cis–trans isomerase (PPIase) enzymes have been shown to be important for virulence in a broad-spectrum of pathogenic bacteria. This Perspective will provide an overview of the recent advances made in understanding the role of each immunophilin family, cyclophilins, FK506 binding proteins (FKBPs), and parvulins in bacteria. Inhibitor design and medicinal chemistry strategies for development of novel drugs against bacterial FKBPs will be discussed. Furthermore, drugs against human cyclophilins and parvulins will be reviewed in their current indication as antiviral and anticancer therapies.

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“…Nonimmunosuppressant semisynthetic analogues of CsA such as Debio 025 and NIM811 (Figure ) maintain inhibition of Cyps but do not bind to calcineurin . However, these inhibitors have unfavorable drug-like characteristics with high molecular weights, limited solubility, and poor bioavailability . Small molecule inhibitors are needed that exhibit high selectivity for CypD over other Cyps, have improved pharmacokinetic/pharmacodynamic (PK/PD) properties, and do not exhibit immunosuppression, to treat acute pancreatitis and other diseases in which mitochondrial dysfunction has a major role.…”

Section: Introductionmentioning

confidence: 99%

Small Molecule Inhibitors of Cyclophilin D To Protect Mitochondrial Function as a Potential Treatment for Acute Pancreatitis

et al. 2016

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Opening of the mitochondrial permeability transition pore (MPTP) causes mitochondrial dysfunction and necrosis in acute pancreatitis (AP), a condition without specific drug treatment. Cyclophilin D (CypD) is a mitochondrial matrix peptidyl-prolyl isomerase that regulates the MPTP and is a drug target for AP. We have synthesized urea-based small molecule inhibitors of cyclophilins and tested them against CypD using binding and isomerase activity assays. Thermodynamic profiles of the CypD/inhibitor interactions were determined by isothermal titration calorimetry. Seven new high-resolution crystal structures of CypD-inhibitor complexes were obtained to guide compound optimization. Compounds 4, 13, 14, and 19 were tested in freshly isolated murine pancreatic acinar cells (PACs) to determine inhibition of toxin-induced loss of mitochondrial membrane potential (ΔΨm) and necrotic cell death pathway activation. Compound 19 was found to have a Kd of 410 nM and a favorable thermodynamic profile, and it showed significant protection of ΔΨm and reduced necrosis of murine as well as human PACs. Compound 19 holds significant promise for future lead optimization.

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Design and Synthesis of Conformationally Constrained Cyclophilin Inhibitors Showing a Cyclosporin‐A Phenotype in C. elegans

Cited by 9 publications

References 39 publications

Fragment-based discovery of a new family of non-peptidic small-molecule cyclophilin inhibitors with potent antiviral activities

Fragment-based discovery of a new family of non-peptidic small-molecule cyclophilin inhibitors with potent antiviral activities

Targeting Protein Folding: A Novel Approach for the Treatment of Pathogenic Bacteria

Small Molecule Inhibitors of Cyclophilin D To Protect Mitochondrial Function as a Potential Treatment for Acute Pancreatitis

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