{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:41:23Z","timestamp":1760060483399,"version":"build-2065373602"},"reference-count":47,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,8,24]],"date-time":"2025-08-24T00:00:00Z","timestamp":1755993600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health","award":["1R21NS128597","MRC J54359","UK DRI-LA2023\/2"],"award-info":[{"award-number":["1R21NS128597","MRC J54359","UK DRI-LA2023\/2"]}]},{"name":"Medical Research Council","award":["1R21NS128597","MRC J54359","UK DRI-LA2023\/2"],"award-info":[{"award-number":["1R21NS128597","MRC J54359","UK DRI-LA2023\/2"]}]},{"name":"Dementia Research Institute","award":["1R21NS128597","MRC J54359","UK DRI-LA2023\/2"],"award-info":[{"award-number":["1R21NS128597","MRC J54359","UK DRI-LA2023\/2"]}]},{"name":"UK Medical Research Council","award":["1R21NS128597","MRC J54359","UK DRI-LA2023\/2"],"award-info":[{"award-number":["1R21NS128597","MRC J54359","UK DRI-LA2023\/2"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Marine Drugs"],"abstract":"<jats:p>While immunophilins are well-recognized therapeutic targets, several members of this family of peptidyl-proline isomerases (PPIases) have yet to be subjected to ligand discovery efforts. In this study, we demonstrate a cost-effective means to identify ligands to the insufficiently investigated two-domain PPIase human Cyclophilin40 (Cyp40). Central to this effort was the use of beads, wherein a confocal nanoscanning (CONA) approach was used to rapidly probe candidates. Here, we describe how one can adapt the physical nature of microsized beads as a means to strategically reduce cost and ultimately make the discovery of small molecule hit and lead compounds more accessible to everyone irrespective of financial status (democratization).<\/jats:p>","DOI":"10.3390\/md23090336","type":"journal-article","created":{"date-parts":[[2025,8,25]],"date-time":"2025-08-25T00:09:53Z","timestamp":1756080593000},"page":"336","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Democratized Discovery of Microsclerodermin F as an Immunophilin Ligand"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8920-3522","authenticated-orcid":false,"given":"Manfred","family":"Auer","sequence":"first","affiliation":[{"name":"Xenobe Research Institute, P.O. Box 3052, San Diego, CA 92163-1052, USA"},{"name":"School of Biological Sciences, University of Edinburgh, The King\u2019s Buildings, Edinburgh EH9 3BF, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5955-9325","authenticated-orcid":false,"given":"Malcolm D.","family":"Walkinshaw","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, University of Edinburgh, Michael Swann Building, Max Born Crescent, Edinburgh EH9 3JR, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacqueline","family":"Dornan","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, University of Edinburgh, Michael Swann Building, Max Born Crescent, Edinburgh EH9 3JR, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1620-2910","authenticated-orcid":false,"given":"Nhan T.","family":"Pham","sequence":"additional","affiliation":[{"name":"Institute for Regeneration and Repair, College of Medicine and Veterinary Medicine, University of Edinburgh, 4-5 Little France Drive, Edinburgh EH16 4UU, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3160-4555","authenticated-orcid":false,"given":"Xinru","family":"Xue","sequence":"additional","affiliation":[{"name":"Institute for Biomedicine and Glycomics, Griffith University, Brisbane, QLD 4111, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0930-3617","authenticated-orcid":false,"given":"Miaomiao","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute for Biomedicine and Glycomics, Griffith University, Brisbane, QLD 4111, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4022-2623","authenticated-orcid":false,"given":"Ronald J.","family":"Quinn","sequence":"additional","affiliation":[{"name":"Institute for Biomedicine and Glycomics, Griffith University, Brisbane, QLD 4111, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric M.","family":"Ross","sequence":"additional","affiliation":[{"name":"Xenobe Research Institute, P.O. Box 3052, San Diego, CA 92163-1052, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abimael D.","family":"Rodr\u00edguez","sequence":"additional","affiliation":[{"name":"Molecular Sciences Research Center, University of Puerto Rico, 1390 Ponce de Le\u00f3n Avenue, San Juan 00926, Puerto Rico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6500-4107","authenticated-orcid":false,"given":"James J.","family":"La Clair","sequence":"additional","affiliation":[{"name":"Xenobe Research Institute, P.O. Box 3052, San Diego, CA 92163-1052, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1007\/s10295-015-1723-5","article-title":"Natural product discovery: Past, present, and future","volume":"43","author":"Katz","year":"2016","journal-title":"J. Ind. Microbiol. Biotechnol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1021\/acs.jnatprod.9b01285","article-title":"Natural Products as Sources of New Drugs over the Nearly Four Decades from 01\/1981 to 09\/2019","volume":"83","author":"Newmann","year":"2020","journal-title":"J. Nat. Prod."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1038\/s41573-020-00114-z","article-title":"Natural products in drug discovery: Advances and opportunities","volume":"20","author":"Atanasov","year":"2021","journal-title":"Nat. Rev. Drug. Discov."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"101984","DOI":"10.1016\/j.econedurev.2020.101984","article-title":"Technology and educational choices: Evidence from a one-laptop-per-child program","volume":"76","author":"Yanguas","year":"2020","journal-title":"Econ. Educ. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"a2459","DOI":"10.1136\/bmj.a2459","article-title":"Extending the benefits of one laptop per child to health","volume":"337","author":"Fontelo","year":"2008","journal-title":"BMJ"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1038\/nature09796","article-title":"A decade\u2019s perspective on DNA sequencing technology","volume":"470","author":"Marris","year":"2011","journal-title":"Nature"},{"key":"ref_7","unstructured":"Wetterstrand, K.A. (2025, February 27). DNA Sequencing Costs: Data from the NHGRI Genome Sequencing Program (GSP), Available online: www.genome.gov\/sequencingcostsdata."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1348","DOI":"10.1021\/ed1003806","article-title":"A graphical journey of innovative organic architectures that have improved our lives","volume":"87","author":"McGrath","year":"2010","journal-title":"J. Chem. Educ."},{"key":"ref_9","unstructured":"(2025, February 27). Top 200 Posters Njardarson Laboratory. Available online: https:\/\/sites.arizona.edu\/njardarson-lab\/top200-posters\/."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Gaud\u00eancio, S.P., Bayram, E., Luki\u0107 Bilela, L., Cueto, M., D\u00edaz-Marrero, A.R., Haznedaroglu, B.Z., Jimenez, C., Mandalakis, M., Pereira, F., and Reyes, F. (2023). Advanced Methods for Natural Products Discovery: Bioactivity Screening, Dereplication, Metabolomics Profiling, Genomic Sequencing, Databases and Informatic Tools, and Structure Elucidation. Mar. Drugs, 21.","DOI":"10.3390\/md21050308"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1039\/C9NP00006B","article-title":"Natural products targeting strategies involving molecular networking: Different manners, one goal","volume":"36","author":"Evanno","year":"2019","journal-title":"Nat. Prod. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.tips.2016.10.011","article-title":"Molecular Networking as a Drug Discovery, Drug Metabolism, and Precision Medicine Strategy","volume":"37","author":"Quinn","year":"2017","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1038\/s41573-022-00414-6","article-title":"Strategies to access biosynthetic novelty in bacterial genomes for drug discovery","volume":"21","author":"Hemmerling","year":"2022","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Saboti\u010d, J., Bayram, E., Ezra, D., Gaud\u00eancio, S.P., Haznedaro\u011flu, B.Z., Jane\u017e, N., Ktari, L., Luganini, A., Mandalakis, M., and Safarik, I. (2024). A guide to the use of bioassays in exploration of natural resources. Biotechnol. Adv., 71.","DOI":"10.1016\/j.biotechadv.2024.108307"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Albarano, L., Esposito, R., Ruocco, N., and Costantini, M. (2020). Genome Mining as New Challenge in Natural Products Discovery. Mar. Drugs., 18.","DOI":"10.3390\/md18040199"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2100","DOI":"10.1039\/D1NP00032B","article-title":"Genome mining methods to discover bioactive natural products","volume":"38","author":"Bauman","year":"2021","journal-title":"Nat. Prod. Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1039\/D0CB00122H","article-title":"A two-step resin based approach to reveal survivin-selective fluorescent probes","volume":"2","author":"Ambrose","year":"2020","journal-title":"RSC Chem. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Wang, P., and Heitman, J. (2005). The cyclophilins. Genome Biol., 6.","DOI":"10.1186\/gb-2005-6-7-226"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e202201597","DOI":"10.1002\/anie.202201597","article-title":"Non-immunosuppressive Cyclophilin inhibitors","volume":"61","author":"Fischer","year":"2022","journal-title":"Angew. Chem. Int. Ed. Engl."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1159\/000123041","article-title":"FKBP family proteins: Immunophilins with versatile biological functions","volume":"16","author":"Kang","year":"2008","journal-title":"Neurosignals"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1016\/j.coph.2011.04.007","article-title":"Targeting FKBP isoforms with small-molecule ligands","volume":"11","author":"Blackburn","year":"2011","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2005","DOI":"10.1016\/j.bbagen.2014.11.012","article-title":"Multidomain Peptidyl Prolyl cis\/trans Isomerases","volume":"1850","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/j.cld.2009.05.002","article-title":"Cyclophilin inhibitors","volume":"13","author":"Gallay","year":"2009","journal-title":"Clin. Liver Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1016\/j.bbrc.2012.07.024","article-title":"Cyclophilin A and viral infections","volume":"424","author":"Zhou","year":"2012","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1895","DOI":"10.1016\/j.drudis.2022.05.016","article-title":"Repurposing of cyclophilin A inhibitors as broad-spectrum antiviral agents","volume":"27","author":"Han","year":"2022","journal-title":"Drug Discov. Today"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/j.ijpara.2005.11.003","article-title":"Peptidyl-prolyl cis\u2013trans isomerases (immunophilins) and their roles in parasite biochemistry, host\u2013parasite interaction and antiparasitic drug action","volume":"36","author":"Bell","year":"2006","journal-title":"Int. J. Parasitol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Jin, S., Zhang, M., and Qiao, X. (2024). Cyclophilin A: Promising target in cancer therapy. Cancer Biol. Ther., 25.","DOI":"10.1080\/15384047.2024.2425127"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"37","DOI":"10.2174\/1874467208666150519113427","article-title":"Immunophilins: Structures, Mechanisms and Ligands","volume":"9","author":"Harikishore","year":"2015","journal-title":"Curr. Mol. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1006\/geno.1996.0384","article-title":"The structure and complete nucleotide sequence of the human cyclophilin 40 (PPID) gene","volume":"35","author":"Yokoi","year":"1996","journal-title":"Genomics"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1021\/np900009b","article-title":"Structure Elucidation at the Nanomole-Scale. 3. Phorbasides G-I from Phorbas sp.","volume":"72","author":"Dalisay","year":"2009","journal-title":"J. Nat. Prod."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3679","DOI":"10.1016\/S0040-4020(00)00286-6","article-title":"Microsclerodermins F\u2013I, Antitumor and Antifungal Cyclic Peptides from the Lithistid Sponge Microscleroderma sp.","volume":"57","author":"Qureshi","year":"2000","journal-title":"Tetrahedron"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2630","DOI":"10.1021\/acs.jnatprod.3c00636","article-title":"Discovery of Anti-SARS-CoV-2 Nsp9 Binders from Natural Products by a Native Mass Spectrometry Approach","volume":"86","author":"Quinn","year":"2023","journal-title":"J. Nat. Prod."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1021\/acsbiomedchemau.2c00021","article-title":"Collision-Induced Affinity Selection Mass Spectrometry for Identification of Ligands","volume":"2","author":"Mak","year":"2022","journal-title":"ACS Bio Med Chem Au"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.1080\/17460441.2019.1653849","article-title":"Fragment-based screening with natural products for novel anti-parasitic disease drug discovery","volume":"14","author":"Quinn","year":"2019","journal-title":"Expert. Opin. Drug Discov."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1021\/acsptsci.2c00225","article-title":"Drug-Repurposing Screening Identifies a Gallic Acid Binding Site on SARS-CoV-2 Non-structural Protein 7","volume":"6","author":"Gu","year":"2023","journal-title":"ACS Pharmacol. Transl. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Liu, M., Van Voorhis, W.C., and Quinn, R.J. (2021). Development of a target identification approach using native mass spectrometry. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-81859-4"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Elnaas, A.R., Grice, D., Han, J., Feng, Y., Capua, A.D., Mak, T., Laureanti, J.A., Buchko, G.W., Myler, P.J., and Cook, G. (2020). Discovery of a Natural Product That Binds to the Mycobacterium tuberculosis Protein Rv1466 Using Native Mass Spectrometry. Molecules, 25.","DOI":"10.3390\/molecules25102384"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Zhao, X., Zhao, X., Di, W., and Wang, C. (2024). Inhibitors of Cyclophilin A: Current and Anticipated Pharmaceutical Agents for Inflammatory Diseases and Cancers. Molecules, 29.","DOI":"10.3390\/molecules29061235"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/0009-9120(91)90105-N","article-title":"Cyclosporine analogues","volume":"24","author":"Jeffery","year":"1991","journal-title":"Clin. Biochem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"5348","DOI":"10.1002\/anie.200352423","article-title":"Total synthesis of microsclerodermin E","volume":"42","author":"Zhu","year":"2003","journal-title":"Angew. Chem. Int. Ed. Engl."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"9753","DOI":"10.1002\/anie.201604764","article-title":"Dehydromicrosclerodermin B and Microsclerodermin J: Total Synthesis and Structural Revision","volume":"55","author":"Melikhova","year":"2016","journal-title":"Angew. Chem. Int. Ed. Engl."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1007\/s10637-014-0185-3","article-title":"The marine natural product microsclerodermin A is a novel inhibitor of the nuclear factor kappa B and induces apoptosis in pancreatic cancer cells","volume":"33","author":"Maers","year":"2015","journal-title":"Investig. New Drugs"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"16904","DOI":"10.1021\/ja4054509","article-title":"Microsclerodermins from terrestrial myxobacteria: An intriguing biosynthesis likely connected to a sponge symbiont","volume":"135","author":"Hoffmann","year":"2013","journal-title":"J. Am. Chem. Soc."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Ye, Y.Q., Zhang, X.Y., Gong, H.N., Ye, M.Q., and Du, Z.J. (2025). Description of Hyphococcus formosus sp. nov. and Hyphococcus lacteus sp. nov., isolated from coastal sediment, and reclassification of Marinicaulis flavus as Hyphococcus luteus nom. nov. and Marinicaulis aureus as Hyphococcus aureus comb. nov. Syst. Appl. Microbiol., 48.","DOI":"10.1016\/j.syapm.2024.126575"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Blackburn, E.A., Wear, M.A., Landr\u00e9, V., Narayan, V., Ning, J., Erman, B., Ball, K.L., and Walkinshaw, M.D. (2015). Cyclophilin40 isomerase activity is regulated by a temperature-dependent allosteric interaction with Hsp90. Biosci. Rep., 35.","DOI":"10.1042\/BSR20150124"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.ab.2005.06.037","article-title":"A surface plasmon resonance-based assay for small molecule inhibitors of human cyclophilin A","volume":"345","author":"Wear","year":"2005","journal-title":"Anal. Biochem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1441","DOI":"10.1021\/acs.bioconjchem.4c00345","article-title":"Novel Confocal Scanning Protein\u2013Protein Interaction Assay (PPI-CONA) Reveals Exceptional Selectivity and Specificity of CC0651, a Small Molecule Binding Enhancer of the Weak Interaction between the E2 Ubiquitin-Conjugating Enzyme CDC34A and Ubiquitin","volume":"35","author":"Koszela","year":"2024","journal-title":"Bioconjug. Chem."}],"container-title":["Marine Drugs"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-3397\/23\/9\/336\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:35:23Z","timestamp":1760034923000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-3397\/23\/9\/336"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,24]]},"references-count":47,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["md23090336"],"URL":"https:\/\/doi.org\/10.3390\/md23090336","relation":{},"ISSN":["1660-3397"],"issn-type":[{"type":"electronic","value":"1660-3397"}],"subject":[],"published":{"date-parts":[[2025,8,24]]}}}