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Characterization of SPP inhibitors suppressing propagation of HCV and protozoa

  1. Yoshiharu Matsuuraa,1
  1. aDepartment of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan;
  2. bDepartment of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan;
  3. cDepartment of Molecular Protozoology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan;
  4. dPlanning and Promotion Office for University-Industry Collaboration, Osaka University, Osaka 565-0871, Japan;
  5. eKOTAI Biotechnologies, Inc., Osaka, Japan;
  6. fDepartment of Veterinary Pathology, Yamaguchi University, Yamaguchi 753-0841, Japan;
  7. gDepartment of Genome Informatics, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan;
  8. hDepartment of Microbiology, Faculty of Medicine, University of Yamanashi, Yamanashi 400-8510, Japan;
  9. iDepartment of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8654, Japan
  1. Edited by Peter Palese, Icahn School of Medicine at Mount Sinai, New York, NY, and approved November 3, 2017 (received for review July 17, 2017)

Significance

Signal peptide peptidase (SPP) is an essential host factor for propagation of hepatitis C virus (HCV). Here, we show that dibenzoazepine-type γ-secretase inhibitors suppressed the maturation of all genotypes of HCV core proteins through a specific interaction with Val223 in SPP, and no drug-resistant virus emerged after several passages of HCV in the presence of the SPP inhibitors. In addition, SPP encoded by Plasmodium falciparum was functionally similar to human SPP, and treatment with the SPP inhibitors suppressed the propagation of protozoa, including P. falciparum and Toxoplasma gondii. Structural analysis in silico revealed that Phe258 of SPP participates in binding to the inhibitors. Compounds possessing a high affinity to Val223/Phe258 in SPP might be novel therapeutics for chronic hepatitis C and protozoiasis.

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.

Footnotes

  • ?1To whom correspondence may be addressed. Email: toru{at}biken.osaka-u.ac.jp or matsuura{at}biken.osaka-u.ac.jp.
  • Author contributions: T.O. and Y. Matsuura designed research; J.H., T.O., Y. Sugiyama, T.S., S.K., M.T., T.F., M.S., T.T., and Y. Sakai performed research; M.S., T.T., Y. Matsunaga, K.Y., M.Y., T.H., D.M.S., K. Moriishi, K. Moriya, and K.K. contributed new reagents/analytic tools; K. Moriishi analyzed data; and J.H., T.O., and Y. Matsuura wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.danielhellerman.com/lookup/suppl/doi:10.1073/pnas.1712484114/-/DCSupplemental.

Published under the PNAS license.

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