Drug Targets and Molecular Mechanisms of Drug Resistance in Chronic Hepatitis B

Marc Ghany, T. Jake Liang

Research output: Contribution to journalArticle

Abstract

Chronic hepatitis B continues to be a major cause of end-stage liver disease and hepatocellular carcinoma worldwide. Nucleos(t)ide analogues have proven to be effective in controlling the disease and perhaps decreasing the incidence of hepatocellular carcinoma. However, development of drug resistance is a major limitation to their long-term effectiveness. Understanding the mechanisms of drug resistance are important for designing new agents and devising strategies to manage and prevent the development of antiviral drug resistance. The development of resistance is determined by an interplay of viral, host, and drug characteristics Homology of the HBV polymerase to the human immunodeficiency virus-1 reverse transcriptase has allowed predictions to be made on the effect mutations have on HBV polymerase structure. In vitro functional studies provide complementary information. Several broad principles on the mechanism of resistance have emerged from these studies. First, most of the primary mutations cluster in the vicinity of the incoming nucleotide and act by directly affecting the position or stability of the bound substrate, template, or primer. In contrast, secondary mutations tend to occur away from the nucleotide-binding pocket. Finally, the structural and functional consequences of mutations are quite variable among the different agents. This paper reviews the key mutations and mechanisms associated with resistance to the nucleos(t)ide analogues approved for clinical use and discuss new targets for drug development.

Original languageEnglish (US)
Pages (from-to)1574-1585
Number of pages12
JournalGastroenterology
Volume132
Issue number4
DOIs
StatePublished - Apr 2007
Externally publishedYes

Fingerprint

Chronic Hepatitis B
Drug Resistance
Mutation
Pharmaceutical Preparations
Hepatocellular Carcinoma
Viral Drug Resistance
Nucleotides
End Stage Liver Disease
Incidence
Hepatitis B virus P protein

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Drug Targets and Molecular Mechanisms of Drug Resistance in Chronic Hepatitis B. / Ghany, Marc; Liang, T. Jake.

In: Gastroenterology, Vol. 132, No. 4, 04.2007, p. 1574-1585.

Research output: Contribution to journalArticle

Ghany, Marc ; Liang, T. Jake. / Drug Targets and Molecular Mechanisms of Drug Resistance in Chronic Hepatitis B. In: Gastroenterology. 2007 ; Vol. 132, No. 4. pp. 1574-1585.
@article{276384a4f61c4998998bf4a918b40546,
title = "Drug Targets and Molecular Mechanisms of Drug Resistance in Chronic Hepatitis B",
abstract = "Chronic hepatitis B continues to be a major cause of end-stage liver disease and hepatocellular carcinoma worldwide. Nucleos(t)ide analogues have proven to be effective in controlling the disease and perhaps decreasing the incidence of hepatocellular carcinoma. However, development of drug resistance is a major limitation to their long-term effectiveness. Understanding the mechanisms of drug resistance are important for designing new agents and devising strategies to manage and prevent the development of antiviral drug resistance. The development of resistance is determined by an interplay of viral, host, and drug characteristics Homology of the HBV polymerase to the human immunodeficiency virus-1 reverse transcriptase has allowed predictions to be made on the effect mutations have on HBV polymerase structure. In vitro functional studies provide complementary information. Several broad principles on the mechanism of resistance have emerged from these studies. First, most of the primary mutations cluster in the vicinity of the incoming nucleotide and act by directly affecting the position or stability of the bound substrate, template, or primer. In contrast, secondary mutations tend to occur away from the nucleotide-binding pocket. Finally, the structural and functional consequences of mutations are quite variable among the different agents. This paper reviews the key mutations and mechanisms associated with resistance to the nucleos(t)ide analogues approved for clinical use and discuss new targets for drug development.",
author = "Marc Ghany and Liang, {T. Jake}",
year = "2007",
month = "4",
doi = "10.1053/j.gastro.2007.02.039",
language = "English (US)",
volume = "132",
pages = "1574--1585",
journal = "Gastroenterology",
issn = "0016-5085",
publisher = "W.B. Saunders Ltd",
number = "4",

}

TY - JOUR

T1 - Drug Targets and Molecular Mechanisms of Drug Resistance in Chronic Hepatitis B

AU - Ghany, Marc

AU - Liang, T. Jake

PY - 2007/4

Y1 - 2007/4

N2 - Chronic hepatitis B continues to be a major cause of end-stage liver disease and hepatocellular carcinoma worldwide. Nucleos(t)ide analogues have proven to be effective in controlling the disease and perhaps decreasing the incidence of hepatocellular carcinoma. However, development of drug resistance is a major limitation to their long-term effectiveness. Understanding the mechanisms of drug resistance are important for designing new agents and devising strategies to manage and prevent the development of antiviral drug resistance. The development of resistance is determined by an interplay of viral, host, and drug characteristics Homology of the HBV polymerase to the human immunodeficiency virus-1 reverse transcriptase has allowed predictions to be made on the effect mutations have on HBV polymerase structure. In vitro functional studies provide complementary information. Several broad principles on the mechanism of resistance have emerged from these studies. First, most of the primary mutations cluster in the vicinity of the incoming nucleotide and act by directly affecting the position or stability of the bound substrate, template, or primer. In contrast, secondary mutations tend to occur away from the nucleotide-binding pocket. Finally, the structural and functional consequences of mutations are quite variable among the different agents. This paper reviews the key mutations and mechanisms associated with resistance to the nucleos(t)ide analogues approved for clinical use and discuss new targets for drug development.

AB - Chronic hepatitis B continues to be a major cause of end-stage liver disease and hepatocellular carcinoma worldwide. Nucleos(t)ide analogues have proven to be effective in controlling the disease and perhaps decreasing the incidence of hepatocellular carcinoma. However, development of drug resistance is a major limitation to their long-term effectiveness. Understanding the mechanisms of drug resistance are important for designing new agents and devising strategies to manage and prevent the development of antiviral drug resistance. The development of resistance is determined by an interplay of viral, host, and drug characteristics Homology of the HBV polymerase to the human immunodeficiency virus-1 reverse transcriptase has allowed predictions to be made on the effect mutations have on HBV polymerase structure. In vitro functional studies provide complementary information. Several broad principles on the mechanism of resistance have emerged from these studies. First, most of the primary mutations cluster in the vicinity of the incoming nucleotide and act by directly affecting the position or stability of the bound substrate, template, or primer. In contrast, secondary mutations tend to occur away from the nucleotide-binding pocket. Finally, the structural and functional consequences of mutations are quite variable among the different agents. This paper reviews the key mutations and mechanisms associated with resistance to the nucleos(t)ide analogues approved for clinical use and discuss new targets for drug development.

UR - http://www.scopus.com/inward/record.url?scp=34247222010&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34247222010&partnerID=8YFLogxK

U2 - 10.1053/j.gastro.2007.02.039

DO - 10.1053/j.gastro.2007.02.039

M3 - Article

C2 - 17408658

AN - SCOPUS:34247222010

VL - 132

SP - 1574

EP - 1585

JO - Gastroenterology

JF - Gastroenterology

SN - 0016-5085

IS - 4

ER -