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Characterization of SPP inhibitors suppressing propagation of HCV and protozoa
Junki Hirano1, Toru Okamoto2, Yukari Sugiyama1
1Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
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.
Insights
Signal peptide peptidase (SPP) inhibitors, particularly those with a dibenzoazepine structure, effectively block hepatitis C virus (HCV) replication. This novel therapeutic approach also shows promise against protozoan infections.
Area of Science:
- Biochemistry
- Virology
- Parasitology
Background:
- Signal peptide peptidase (SPP) is an intramembrane aspartic protease crucial for hepatitis C virus (HCV) core protein maturation.
- SPP activity is implicated in HCV propagation and pathogenesis.
Purpose of the Study:
- To investigate the inhibitory activity of gamma-secretase inhibitors against SPP.
- To identify structural features of inhibitors critical for SPP inhibition.
- To evaluate the therapeutic potential of SPP inhibitors against HCV and protozoan infections.
Main Methods:
- Screening of gamma-secretase inhibitors for SPP inhibitory activity.
- In vitro and in vivo assays to assess the efficacy of lead compound YO-01027.
- Analysis of drug-resistance emergence compared to direct-acting antivirals.
- Testing YO-01027 against Plasmodium falciparum and Toxoplasma gondii.
Main Results:
- The dibenzoazepine structural motif in gamma-secretase inhibitors is key for SPP inhibition.
- Compound YO-01027 demonstrated potent in vitro and in vivo SPP inhibition via interaction with Val223.
- SPP inhibition by YO-01027 suppressed all HCV genotypes without resistance development.
- YO-01027 effectively inhibited Plasmodium falciparum and Toxoplasma gondii propagation.
Conclusions:
- SPP is a validated therapeutic target for chronic hepatitis C.
- SPP inhibitors like YO-01027 offer a promising strategy against HCV, circumventing resistance issues seen with current antivirals.
- SPP inhibition presents a potential treatment avenue for protozoan diseases like malaria and toxoplasmosis.
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