NDLI: Evaluating the Role of Macrocycles in the Susceptibility of Hepatitis C Virus NS3/4A Protease Inhibitors to Drug Resistance

Please wait, while we are loading the content...

Quantification of cellular poly(ADP-ribosyl)ation by stable isotope dilution massspectrometry reveals tissue- and drug-dependent stress response dynamics

Proteome-wide reactivity profiling identifies diverse carbamate chemotypes tuned for serine hydrolase inhibition

Allosteric Communication in the KIX Domain Proceedsthrough Dynamic Repacking of the Hydrophobic Core

Stable RAGE-Heparan Sulfate Complexes are Essential for Signal Transduction

Structural and functional characterization of CalS11, a TDP-rhamnose 3′-O-methyltransferase involved in calicheamicin biosynthesis

An Expanded Genetic Code In Mammalian Cells With A Functional Quadruplet Codon

Year: 2013, Volume: 8, Issue: 6

Year: 2013, Volume: 8, Issue: 5

Year: 2013, Volume: 8, Issue: 4

Year: 2013, Volume: 8, Issue: 3

Year: 2013, Volume: 8, Issue: 2

Year: 2013, Volume: 8, Issue: 1

Year: 2012, Volume: 7

Year: 2011, Volume: 6

Year: 2010, Volume: 5

Year: 2009, Volume: 4

Year: 2008, Volume: 3

Year: 2007, Volume: 2

Year: 2006, Volume: 1

Evaluating the Role of Macrocycles in the Susceptibility of Hepatitis C Virus NS3/4A Protease Inhibitors to Drug Resistance

Content Provider	PubMed Central
Author	Ali, Akbar Aydin, Cihan Gildemeister, Reinhold Romano, Keith P. Cao, Hong Özen, Ayşegül Soumana, Djade Newton, Alicia Petropoulos, Christos J. Huang, Wei Schiffer, Celia A.
Abstract	The hepatitis C virus (HCV) infects an estimated 150 million people worldwide and is the major cause of viral hepatitis, cirrhosis and liver cancer. The available antiviral therapies, which include pegylated-interferon, ribavirin and one of the HCV NS3/4A protease inhibitors telaprevir or boceprevir, are ineffective for some patients and cause severe side effects. More potent NS3/4A protease inhibitors are in clinical development, but the long-term effectiveness of these drugs is challenged by the development of drug resistance. Here, we investigated the role of macrocycles in the susceptibility of NS3/4A protease inhibitors to drug resistance in asunaprevir, danoprevir, vaniprevir, and MK-5172, with similar core structures but varied P2 moieties and macrocyclizations. Linear and macrocyclic analogues of these drugs were designed, synthesized and tested against wild-type and drug-resistant variants R155K, V36M/R155K, A156T, and D168A in enzymatic and antiviral assays. Macrocyclic inhibitors were generally more potent, but the location of the macrocycle was critical for retaining activity against drug-resistant variants – the P1–P3 macrocyclic inhibitors were less susceptible to drug resistance than the linear and P2–P4 macrocyclic analogues. In addition, the heterocyclic moiety at P2 largely determined the inhibitor resistance profile, susceptibility to drug resistance, and the extent of modulation by the helicase domain. Our findings suggest that to design robust inhibitors that retain potency to drug resistant NS3/4A protease variants, inhibitors should combine P1–P3 macrocycles with flexible P2 moieties that optimally contact with the invariable catalytic triad of this enzyme.
Related Links	http://dx.doi.org/10.1021/cb400100g
Ending Page	1478
Page Count	10
Starting Page	1469
File Format	PDF
ISSN	15548929
e-ISSN	15548937
Journal	ACS chemical biology
Issue Number	7
Volume Number	8
Language	English
Publisher Date	2013-07-19
Access Restriction	Open
Subject Keyword	Molecular Medicine Biochemistry Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Medicine Biochemistry Molecular Medicine

Sl.	Authority	Responsibilities	Communication Details
1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
5	Website/Portal (Helpdesk)	Queries regarding NDLI and its services	support@ndl.gov.in
6	Contents and Copyright Issues	Queries related to content curation and copyright issues	content@ndl.gov.in
7	National Digital Library of India Club (NDLI Club)	Queries related to NDLI Club formation, support, user awareness program, seminar/symposium, collaboration, social media, promotion, and outreach	clubsupport@ndl.gov.in
8	Digital Preservation Centre (DPC)	Assistance with digitizing and archiving copyright-free printed books	dpc@ndl.gov.in
9	IDR Setup or Support	Queries related to establishment and support of Institutional Digital Repository (IDR) and IDR workshops	idr@ndl.gov.in

Molecular Mechanism by Which a Potent Hepatitis C Virus NS3-NS4A Protease Inhibitor Overcomes Emergence of Resistance

The Molecular Basis of Drug Resistance against Hepatitis C Virus NS3/4A Protease Inhibitors

High Affinity Peptide Inhibitors of the Hepatitis C Virus NS3-4A Protease Refractory to Common Resistant Mutants

High Affinity Peptide Inhibitors of the Hepatitis C Virus NS3-4A Protease Refractory to Common Resistant Mutants

Computer-aided identification of a series of novel ligands showing high potency as hepatitis C virus NS3/4A protease inhibitors

Molecular basis of telaprevir resistance due to V36 and T54 mutations in the NS3-4A protease of the hepatitis C virus

Unraveling the structural basis of grazoprevir potency against clinically relevant substitutions in hepatitis C virus NS3/4A protease from genotype 1a

Hepatitis C Virus NS3/4A Protease Inhibitors: A Light at the End of the Tunnel

Discovery of MK-5172,a Macrocyclic Hepatitis C Virus NS3/4a Protease Inhibitor

Evaluating the Role of Macrocycles in the Susceptibility of Hepatitis C Virus NS3/4A Protease Inhibitors to Drug Resistance

Similar Documents

Molecular Mechanism by Which a Potent Hepatitis C Virus NS3-NS4A Protease Inhibitor Overcomes Emergence of Resistance

The Molecular Basis of Drug Resistance against Hepatitis C Virus NS3/4A Protease Inhibitors

High Affinity Peptide Inhibitors of the Hepatitis C Virus NS3-4A Protease Refractory to Common Resistant Mutants

High Affinity Peptide Inhibitors of the Hepatitis C Virus NS3-4A Protease Refractory to Common Resistant Mutants

Computer-aided identification of a series of novel ligands showing high potency as hepatitis C virus NS3/4A protease inhibitors

Molecular basis of telaprevir resistance due to V36 and T54 mutations in the NS3-4A protease of the hepatitis C virus

Unraveling the structural basis of grazoprevir potency against clinically relevant substitutions in hepatitis C virus NS3/4A protease from genotype 1a

Hepatitis C Virus NS3/4A Protease Inhibitors: A Light at the End of the Tunnel

Discovery of MK-5172,a Macrocyclic Hepatitis C Virus NS3/4a Protease Inhibitor

Evaluating the Role of Macrocycles in the Susceptibility of Hepatitis C Virus NS3/4A Protease Inhibitors to Drug Resistance