ABSTRACT
Signal peptide peptidase (SPP) is an intramembrane aspartic protease involved in the maturation of the core protein of hepatitis C virus (HCV). The processing of HCV core protein by SPP has been reported to be critical for the propagation and pathogenesis of HCV. Here we examined the inhibitory activity of inhibitors for γ-secretase, another intramembrane cleaving protease, against SPP, and our findings revealed that the dibenzoazepine-type structure in the γ-secretase inhibitors is critical for the inhibition of SPP. The spatial distribution showed that the γ-secretase inhibitor compound YO-01027 with the dibenzoazepine structure exhibits potent inhibiting activity against SPP in vitro and in vivo through the interaction of Val223 in SPP. Treatment with this SPP inhibitor suppressed the maturation of core proteins of all HCV genotypes without the emergence of drug-resistant viruses, in contrast to the treatment with direct-acting antivirals. YO-01027 also efficiently inhibited the propagation of protozoa such as Plasmodium falciparum and Toxoplasma gondii These data suggest that SPP is an ideal target for the development of therapeutics not only against chronic hepatitis C but also against protozoiasis.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Antiprotozoal Agents/pharmacology , Antiviral Agents/pharmacology , Aspartic Acid Endopeptidases/antagonists & inhibitors , Dibenzazepines/pharmacology , Hepacivirus/drug effects , Protease Inhibitors/pharmacology , Animals , Antiprotozoal Agents/chemistry , Antiviral Agents/chemistry , Cell Line , Dibenzazepines/chemistry , HEK293 Cells , Hepacivirus/genetics , Humans , Mice , Mice, Inbred BALB C , Models, Molecular , Plasmodium falciparum/drug effects , Protease Inhibitors/chemistry , Structure-Activity Relationship , Toxoplasma/drug effects , Viral Core Proteins/antagonists & inhibitors , Virus Replication/drug effectsABSTRACT
A novel kappa opioid receptor binding inhibitor CJ-15,208 (I) was isolated from the fermentation broth of a fungus, Ctenomyces serratus ATCC15502. The structure of I was determined to be a cyclic tetrapeptide consisting of one tryptophan, one D-proline, and two L-phenylalanine. Compound I was a selective binding inhibitor for the kappa opioid receptor: 47 nM (IC50) for kappa, 260 nM for mu, and 2,600 nM for delta. In the electrically-stimulated twitch response assay of rabbit vas deferens I recovered the suppression by a kappa agonist asimadoline with an ED50 of 1.3 microM, indicating that it is a kappa antagonist.
