2. Academic Validation
  3. Characterization of SPP inhibitors suppressing propagation of HCV and protozoa

Characterization of SPP inhibitors suppressing propagation of HCV and protozoa

  • Proc Natl Acad Sci U S A. 2017 Dec 12;114(50):E10782-E10791. doi: 10.1073/pnas.1712484114.
Junki Hirano 1,  Toru Okamoto 2,  Yukari Sugiyama 1,  Tatsuya Suzuki 1,  Shinji Kusakabe 1,  Makoto Tokunaga 1,  Takasuke Fukuhara 1,  Miwa Sasai 3,  Takahiro Tougan 4,  Yasue Matsunaga 5,  Kazuo Yamashita 6,  Yusuke Sakai 7,  Masahiro Yamamoto 3,  Toshihiro Horii 4,  Daron M Standley 8,  Kohji Moriishi 9,  Kyoji Moriya 10,  Kazuhiko Koike 10,  Yoshiharu Matsuura 2
Affiliations

Affiliations

  • 1 Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
  • 2 Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan; [email protected] [email protected].
  • 3 Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
  • 4 Department of Molecular Protozoology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
  • 5 Planning and Promotion Office for University-Industry Collaboration, Osaka University, Osaka 565-0871, Japan.
  • 6 KOTAI Biotechnologies, Inc., Osaka, Japan.
  • 7 Department of Veterinary Pathology, Yamaguchi University, Yamaguchi 753-0841, Japan.
  • 8 Department of Genome Informatics, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
  • 9 Department of Microbiology, Faculty of Medicine, University of Yamanashi, Yamanashi 400-8510, Japan.
  • 10 Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8654, Japan.
PMID: 29187532 DOI: 10.1073/pnas.1712484114
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.

Keywords

HCV; Protozoa; SPP; pathogenesis; propagation.

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