Abstract
BackgroundFurin represents a crucial member of secretory mammalian subtilase, the Proprotein Convertase (PC) or Proprotein Convertase Subtilisin/Kexin (PCSK) superfamily. It has been linked to cancer, tumorgenesis, viral and bacterial pathogenesis. As a result it is considered a major target for intervention of these diseases.Methodology/Principal FindingsHerein, we report, for the first time, the synthesis and biological evaluation of a newly designed potent furin inhibitor that contains a highly reactive beta-turn inducing and radical generating “enediynyl amino acid” (Eda) moiety. “Eda” was inserted between P1 and P1′ residues of hfurin98–112 peptide, derived from the primary cleavage site of furin's own prodomain. The resulting hexadecapeptide derivative inhibited furin in vitro with IC50 ∼40 nM when measured against the fluorogenic substrate Boc-RVRR-MCA. It also inhibited furin-mediated cleavage of a fluorogenic peptide derived from hSARS-CoV spike protein with IC50 ∼193 nM. Additionally it also blocked furin-processing of growth factors proPDGF-A, B and VEGF-C that are linked to tumor genesis and cancer. Circular dichroism study showed that this inhibitor displayed a predominantly beta-turn structure while western blots confirmed its ability to protect furin protein from self degradation.Conclusion/SignificanceThese findings imply its potential as a therapeutic agent for intervention of cancer and other furin-associated diseases.
Highlights
Furin is a crucial member of Ca+2-dependent mammalian subtilases collectively known as Proprotein Convertases (PCs) or Proprotein Convertase Subtilisin/Kexins (PCSKs)
It is a possibility that these reactive intermediates may react with one or more of the catalytic amino acid residues His, Ser or Asp of PC-enzymes leading to chemical modifications of latter
Except for minor protease activating effect of AB-3 towards PC7, all other enediyne compounds exhibited inhibitory effects towards furin, PC5 and PC7 with IC50 values ranging from 8.5 to 160 mM depending on the nature of the enzyme and the enediyne compound used
Summary
Furin is a crucial member of Ca+2-dependent mammalian subtilases collectively known as Proprotein Convertases (PCs) or Proprotein Convertase Subtilisin/Kexins (PCSKs) This membrane bound type 1 protease is responsible for tissue-specific endoproteolytic cleavage of a large variety of inactive protein precursors at the general sequence motif (K/R)(X)n-(R) Q (where n = 0, 2, 4 or 6 and X is usually any amino acid other than Cys), leading to functionally active secretory proteins and polypeptides [1,2,3]. Among the various inhibitor design strategies so far reported, the prodomain approach attracted most attention because of its effectiveness, versatility and sometimes enhanced selectivity [18,26] Besides this approach, incorporation of noncleavable pseudo peptide bond [29] or unnatural amino acid [30] at P1-P19 site of a potent peptide substrate based on prodomain or physiological protein sequence has been used successfully to design inhibitors of PC enzymes. As a result it is considered a major target for intervention of these diseases
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