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X-ray structure of furin (PCSK3) in complex with the biphenyl-derived compound 42 (mi2464)
Structural highlights
FunctionFURIN_HUMAN Furin is likely to represent the ubiquitous endoprotease activity within constitutive secretory pathways and capable of cleavage at the RX(K/R)R consensus motif.[1] Publication Abstract from PubMedThe proprotein convertase (PC) furin emerged as promising drug target for the treatment of numerous infectious diseases, cancer and cystic fibrosis. A recently described nonpeptidic lead structure served as template to develop a new series of PC inhibitors containing a dichlorobiphenyl-derived core segment decorated with a left and right inhibitor arm. The compounds were tested for their inhibitory potency against furin and the structurally related PC7. The most potent compounds inhibited furin with K(i) values <5 nM, whereas most of them were significantly weaker inhibitors of PC7. Only for one compound, a significant potency with a K(i) value of 7.3 nM against PC7 was found. Furthermore, crystal structures of six inhibitors in complex with furin were determined. Selected inhibitors were additionally tested for their antiviral potency against the furin-dependent H7N7 influenza A strain SC35M; a significant antiviral potency was found for compound 9. Design, Synthesis, and Characterization of Dichlorobiphenyl-Derived Inhibitors of the Proprotein Convertase Furin.,Lange RW, Boller C, Loresch M, Bloch K, Bottcher-Friebertshauser E, Brandstetter H, Dahms SO, Steinmetzer T J Med Chem. 2025 Dec 11;68(23):25157-25170. doi: 10.1021/acs.jmedchem.5c02157. , Epub 2025 Nov 30. PMID:41319212[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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