Dataset Information

Potent HCV NS3 Protease Inhibition by a Water-Soluble Phyllanthin Congener.

ABSTRACT: NS3/4A protease of hepatitis C virus (HCV) plays an important role in viral RNA replication. A 1,4-diphenylbutanedicarboxylic acid derivative, namely, phyllanthin, extracted from the leaf of a herbal plant, Phyllanthus amarus, inhibits HCV NS3/4A protease and replication activities. However, the reduced aqueous solubility, high toxicity, and poor oral bioavailability are major impediments with phyllanthin. We herein present a design approach to generate phyllanthin congeners in order to potentiate inhibition activity against protease. The phyllanthin congeners were synthesized by chemical methods and subjected to systematic biological studies. One of the congeners, annotated as D8, is identified as a novel and potent inhibitor of the HCV-NS3/4Aprotease activity in vitro and the viral RNA replication in cell culture. Structural analysis using the computational-based docking approach demonstrated important noncovalent interactions between D8 and the catalytic residues of the viral protease. Furthermore, D8 was found to be significantly nontoxic in cell culture. More importantly, oral administration of D8 in BALB/c mice proved its better tolerability and bioavailability, as compared to native phyllanthin. Taken together, this study reveals a promising candidate for developing anti-HCV therapeutics to control HCV-induced liver diseases.

SUBMITTER: B UR

PROVIDER: S-EPMC7254805 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Potent HCV NS3 Protease Inhibition by a Water-Soluble Phyllanthin Congener.

B Uma Reddy UR Tandon Himani H Pradhan Manoj K MK Adhikesavan Harikrishnan H Srinivasan Narayanaswamy N Das Saumitra S Jayaraman Narayanaswamy N

ACS omega 20200514 20

NS3/4A protease of hepatitis C virus (HCV) plays an important role in viral RNA replication. A 1,4-diphenylbutanedicarboxylic acid derivative, namely, phyllanthin, extracted from the leaf of a herbal plant, <i>Phyllanthus amarus,</i> inhibits HCV NS3/4A protease and replication activities. However, the reduced aqueous solubility, high toxicity, and poor oral bioavailability are major impediments with phyllanthin. We herein present a design approach to generate phyllanthin congeners in order to p ...[more]

PMID: 32478245

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Project description:Hepatitis C virus (HCV) infects millions of people worldwide, causing chronic liver disease that can lead to cirrhosis, hepatocellular carcinoma, and liver transplant. In the last several years, the advent of direct-acting antivirals, including NS3/4A protease inhibitors (PIs), has remarkably improved treatment outcomes of HCV-infected patients. However, selection of resistance-associated substitutions and polymorphisms among genotypes can lead to drug resistance and in some cases treatment failure. A proactive strategy to combat resistance is to constrain PIs within evolutionarily conserved regions in the protease active site. Designing PIs using the substrate envelope is a rational strategy to decrease the susceptibility to resistance by using the constraints of substrate recognition. We successfully designed two series of HCV NS3/4A PIs to leverage unexploited areas in the substrate envelope to improve potency, specifically against resistance-associated substitutions at D168. Our design strategy achieved better resistance profiles over both the FDA-approved NS3/4A PI grazoprevir and the parent compound against the clinically relevant D168A substitution. Crystallographic structural analysis and inhibition assays confirmed that optimally filling the substrate envelope is critical to improve inhibitor potency while avoiding resistance. Specifically, inhibitors that enhanced hydrophobic packing in the S4 pocket and avoided an energetically frustrated pocket performed the best. Thus, the HCV substrate envelope proved to be a powerful tool to design robust PIs, offering a strategy that can be translated to other targets for rational design of inhibitors with improved potency and resistance profiles.IMPORTANCE Despite significant progress, hepatitis C virus (HCV) continues to be a major health problem with millions of people infected worldwide and thousands dying annually due to resulting complications. Recent antiviral combinations can achieve >95% cure, but late diagnosis, low access to treatment, and treatment failure due to drug resistance continue to be roadblocks against eradication of the virus. We report the rational design of two series of HCV NS3/4A protease inhibitors with improved resistance profiles by exploiting evolutionarily constrained regions of the active site using the substrate envelope model. Optimally filling the S4 pocket is critical to avoid resistance and improve potency. Our results provide drug design strategies to avoid resistance that are applicable to other quickly evolving viral drug targets.

Dataset Information

Potent HCV NS3 Protease Inhibition by a Water-Soluble Phyllanthin Congener.

Publications

Potent HCV NS3 Protease Inhibition by a Water-Soluble Phyllanthin Congener.

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