1197 HCV GENOTYPES HAVE DIFFERENT GENETIC BARRIERS IN THE GENERATION OF RESISTANCE MUTATIONS TO PROTEASE INHIBITORS IN ADVANCED CLINICAL DEVELOPMENT

2011 ◽  
Vol 54 ◽  
pp. S473 ◽  
Author(s):  
V. Cento ◽  
C. Mirabelli ◽  
F. Mercurio ◽  
R. Salpini ◽  
S. Dimonte ◽  
...  
Keyword(s):  
Protease Inhibitors ◽  
Clinical Development ◽  
Resistance Mutations ◽  
Hcv Genotypes ◽  
Genetic Barriers

scholarly journals Comparative Study of the Genetic Barriers and Pathways towards Resistance of Selective Inhibitors of Hepatitis C Virus Replication

2011 ◽  
Vol 55 (9) ◽  
pp. 4103-4113 ◽  
Author(s):  
Leen Delang ◽  
Inge Vliegen ◽  
Mathy Froeyen ◽  
Johan Neyts
Keyword(s):  
Drug Resistance ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Comparative Study ◽  
Protease Inhibitors ◽  
Selection Process ◽  
Drug Resistant ◽  
Resistance Mutations ◽  
Polymerase Inhibitors ◽  
Genetic Barriers

ABSTRACTHepatitis C virus (HCV) inhibitors include direct-acting antivirals (DAAs) such as NS3 serine protease inhibitors, nucleoside and nonnucleoside polymerase inhibitors, and host-targeting antivirals (HTAs) such as cyclophilin inhibitors that have been developed in recent years. Drug-resistant HCV variants have been reported bothin vitroand in the clinical setting for most classes of drugs. We report a comparative study in which the genetic barrier to drug resistance of a representative selection of these inhibitors is evaluated employing a number of resistance selection protocols. The NS3 protease inhibitors VX-950 and BILN 2061, the nucleoside polymerase inhibitor 2′-C-methylcytidine, three nonnucleoside polymerase inhibitors (thiophene carboxylic acid, benzimidazole, and benzothiadiazine), and DEB025 were included. For each drug and passage in the selection process, the phenotype and genotype of the drug-resistant replicon were determined. For a number of molecules (BILN 2061 and nonnucleoside inhibitors), drug-resistant variants were readily selected when wild-type replicon-containing cells were directly cultured in the presence of high concentrations of the inhibitor. Resistance to DEB025 could be selected only following a lengthy stepwise selection procedure. For some DAAs, the signature mutations that emerged under inhibitor pressure differed depending on the selection protocol that was employed. Replication fitness of resistant mutants revealed that the C445F mutation in the RNA-dependent RNA polymerase can restore loss of fitness caused by a number of unfit resistance mutations. These data provide important insights into the various pathways leading to drug resistance and allow a direct comparison of the genetic barriers of various HCV drugs.

scholarly journals Comprehensive Screening for Naturally Occurring Hepatitis C Virus Resistance to Direct-Acting Antivirals in the NS3, NS5A, and NS5B Genes in Worldwide Isolates of Viral Genotypes 1 to 6

2016 ◽  
Vol 60 (4) ◽  
pp. 2402-2416 ◽  
Author(s):  
Juan Ángel Patiño-Galindo ◽  
Karina Salvatierra ◽  
Fernando González-Candelas ◽  
F. Xavier López-Labrador
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Direct Acting Antivirals ◽  
Resistance Mutations ◽  
Genetic Barrier ◽  
Hcv Genotypes ◽  
Naturally Occurring ◽  
Genotype 2 ◽  
Genetic Barriers ◽  
Direct Acting

ABSTRACTThere is no comprehensive study available on the natural hepatitis C virus (HCV) polymorphism in sites associated with resistance including all viral genotypes which may present variable susceptibilities to particular direct-acting antivirals (DAAs). This study aimed to analyze the frequencies, genetic barriers, and evolutionary histories of naturally occurring resistance-associated variants (RAVs) in the six main HCV genotypes. A comprehensive analysis of up to 103 RAVs was performed in 2,901, 2,216, and 1,344 HCV isolates for the NS3, NS5A, and NS5B genes, respectively. We report significant intergenotypic differences in the frequencies of natural RAVs for these three HCV genes. In addition, we found a low genetic barrier for the generation of new RAVs, irrespective of the viral genotype. Furthermore, in 1,126 HCV genomes, including sequences spanning the three genes, haplotype analysis revealed a remarkably high frequency of viruses carrying more than one natural RAV to DAAs (53% of HCV-1a, 28.5% of HCV-1b, 67.1% of HCV-6, and 100% of genotype 2, 3, 4, and 5 haplotypes). With the exception of HCV-1a, the most prevalent haplotypes showed RAVs in at least two different viral genes. Finally, evolutionary analyses revealed that, while most natural RAVs appeared recently, others have been efficiently transmitted over time and cluster in well-supported clades. In summary, and despite the observed high efficacy of DAA-based regimens, we show that naturally occurring RAVs are common in all HCV genotypes and that there is an overall low genetic barrier for the selection of resistance mutations. There is a need for natural DAA resistance profiling specific for each HCV genotype.

scholarly journals Dual inhibition of SARS-CoV-2 and human rhinovirus with protease inhibitors in clinical development

2021 ◽  
Vol 187 ◽  
pp. 105020
Author(s):  
Cheng Liu ◽  
Sandro Boland ◽  
Michael D. Scholle ◽  
Dorothee Bardiot ◽  
Arnaud Marchand ◽  
...  
Keyword(s):  
Protease Inhibitors ◽  
Clinical Development ◽  
Human Rhinovirus ◽  
Dual Inhibition

scholarly journals Major drug resistance mutations to HIV-1 protease inhibitors (PI) among patients exposed to PI class failing antiretroviral therapy in São Paulo State, Brazil

PLoS ONE ◽  
2019 ◽  
Vol 14 (10) ◽  
pp. e0223210
Author(s):  
Giselle de Faria Romero Soldi ◽  
Isadora Coutinho Ribeiro ◽  
Cintia Mayumi Ahagon ◽  
Luana Portes Ozório Coelho ◽  
Gabriela Bastos Cabral ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Antiretroviral Therapy ◽  
Protease Inhibitors ◽  
Sao Paulo ◽  
Resistance Mutations ◽  
Paulo State ◽  
Drug Resistance Mutations ◽  
São Paulo State ◽  
Major Drug ◽  
Hiv 1

New Aza-Dipeptide Analogues as Potent and Orally Absorbed HIV-1 Protease Inhibitors:  Candidates for Clinical Development

1998 ◽  
Vol 41 (18) ◽  
pp. 3387-3401 ◽  
Author(s):  
Guido Bold ◽  
Alexander Fässler ◽  
Hans-Georg Capraro ◽  
Robert Cozens ◽  
Thomas Klimkait ◽  
...  
Keyword(s):  
Protease Inhibitors ◽  
Clinical Development ◽  
Dipeptide Analogues ◽  
Hiv 1

scholarly journals Transient HIV-1 Gag–protease interactions revealed by paramagnetic NMR suggest origins of compensatory drug resistance mutations

2016 ◽  
Vol 113 (44) ◽  
pp. 12456-12461 ◽  
Author(s):  
Lalit Deshmukh ◽  
John M. Louis ◽  
Rodolfo Ghirlando ◽  
G. Marius Clore
Keyword(s):  
Drug Resistance ◽  
Protease Inhibitors ◽  
Specific Antigen ◽  
Paramagnetic Nmr ◽  
Cleavage Sites ◽  
Resistance Mutations ◽  
Gag Polyprotein ◽  
Intrinsically Disordered ◽  
Drug Resistance Mutations ◽  
Hiv 1

Cleavage of the group-specific antigen (Gag) polyprotein by HIV-1 protease represents the critical first step in the conversion of immature noninfectious viral particles to mature infectious virions. Selective pressure exerted by HIV-1 protease inhibitors, a mainstay of current anti–HIV-1 therapies, results in the accumulation of drug resistance mutations in both protease and Gag. Surprisingly, a large number of these mutations (known as secondary or compensatory mutations) occur outside the active site of protease or the cleavage sites of Gag (located within intrinsically disordered linkers connecting the globular domains of Gag to one another), suggesting that transient encounter complexes involving the globular domains of Gag may play a role in guiding and facilitating access of the protease to the Gag cleavage sites. Here, using large fragments of Gag, as well as catalytically inactive and active variants of protease, we probe the nature of such rare encounter complexes using intermolecular paramagnetic relaxation enhancement, a highly sensitive technique for detecting sparsely populated states. We show that Gag-protease encounter complexes are primarily mediated by interactions between protease and the globular domains of Gag and that the sites of transient interactions are correlated with surface exposed regions that exhibit a high propensity to mutate in the presence of HIV-1 protease inhibitors.

scholarly journals MK-5172, a Selective Inhibitor of Hepatitis C Virus NS3/4a Protease with Broad Activity across Genotypes and Resistant Variants

2012 ◽  
Vol 56 (8) ◽  
pp. 4161-4167 ◽  
Author(s):  
Vincenzo Summa ◽  
Steven W. Ludmerer ◽  
John A. McCauley ◽  
Christine Fandozzi ◽  
Christine Burlein ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Protease Inhibitors ◽  
Selective Pressure ◽  
Pegylated Interferon ◽  
Therapeutic Agents ◽  
Hepatitis C Virus Infection ◽  
Dosing Regimen ◽  
Once Daily ◽  
Hcv Genotypes

ABSTRACTHCV NS3/4a protease inhibitors are proven therapeutic agents against chronic hepatitis C virus infection, with boceprevir and telaprevir having recently received regulatory approval as add-on therapy to pegylated interferon/ribavirin for patients harboring genotype 1 infections. Overcoming antiviral resistance, broad genotype coverage, and a convenient dosing regimen are important attributes for future agents to be used in combinations without interferon. In this communication, we report the preclinical profile of MK-5172, a novel P2-P4 quinoxaline macrocyclic NS3/4a protease inhibitor currently in clinical development. The compound demonstrates subnanomolar activity against a broad enzyme panel encompassing major hepatitis C virus (HCV) genotypes as well as variants resistant to earlier protease inhibitors. In replicon selections, MK-5172 exerted high selective pressure, which yielded few resistant colonies. In both rat and dog, MK-5172 demonstrates good plasma and liver exposures, with 24-h liver levels suggestive of once-daily dosing. When administered to HCV-infected chimpanzees harboring chronic gt1a or gt1b infections, MK-5172 suppressed viral load between 4 to 5 logs at a dose of 1 mg/kg of body weight twice daily (b.i.d.) for 7 days. Based on its preclinical profile, MK-5172 is anticipated to be broadly active against multiple HCV genotypes and clinically important resistance variants and highly suited for incorporation into newer all-oral regimens.

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