Abstract
Heat-stress cognate 70 (Hsc70) is a host factor that helps hepatitis C virus (HCV) to complete its life cycle in infected hepatocytes. Using Hsc70 as a target for HCV inhibition, a series of novel N-substituted benzyl matrinic/sophoridinic acid derivatives was synthesized and evaluated for their anti-HCV activity in vitro. Among these analogues, compound 7c possessing N-p-methylbenzyl afforded an appealing ability to inhibit HCV replication with SI value over 53. Furthermore, it showed a good oral pharmacokinetic profile with area-under-curve (AUC) of 13.4 µM·h, and a considerably good safety in oral administration in mice (LD50>1000 mg/kg). As 7c suppresses HCV replication via an action mode distinctly different from that of the marketed anti-HCV drugs, it has been selected as a new mechanism anti-HCV candidate for further investigation, with an advantage of no or decreased chance to induce drug-resistant mutations.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alkaloids / adverse effects
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Alkaloids / chemistry*
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Alkaloids / pharmacokinetics
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Alkaloids / pharmacology*
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Animals
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Antiviral Agents / adverse effects
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Antiviral Agents / chemistry
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Antiviral Agents / pharmacokinetics
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Antiviral Agents / pharmacology
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Cell Line
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Down-Regulation / drug effects*
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HSC70 Heat-Shock Proteins / metabolism*
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Hepacivirus / drug effects*
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Hepacivirus / physiology*
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Humans
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Male
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Matrines
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Mice
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Mice, Inbred ICR
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Quinolizines / adverse effects
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Quinolizines / chemistry*
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Quinolizines / pharmacokinetics
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Quinolizines / pharmacology*
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Safety
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Structure-Activity Relationship
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Virus Replication / drug effects*
Substances
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Alkaloids
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Antiviral Agents
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HSC70 Heat-Shock Proteins
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Quinolizines
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Matrines
Grants and funding
This work was supported by Beijing Natural Science Foundation (7121009) and the National S&T Major Special Project on Major New Drug Innovation (2012ZX09103101–037 and 2012ZX09301002–001). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.