Discovery of Novel Highly Potent Hepatitis C Virus NS5A Inhibitor (AV4025)

Ivachtchenko, Alexandre V.; Mitkin, Oleg D.; Yamanushkin, Pavel M.; Кузнецова, И. В.; Буланова, Елена А.; Shevkun, Natalia A.; Koryakova, Angela G.; Karapetian, Ruben N.; Bichko, V.; Trifelenkov, Andrey S.; Kravchenko, Dmitry V.; Vostokova, Natalia; Veselov, Mark S.; Chufarova, Nina V.; Ivanenkov, Yan A.

doi:10.1021/jm500951r

Cited by 15 publications

(18 citation statements)

References 34 publications

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“…They significantly reduce HCVRNA levels and enhance SVR when given in conjunction with PEG-IFN and RBV. They also result in very high SVR rates among patients with genotype 1 infection when given in combination with other direct-acting antivirals with or without RBV [105] . …”

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confidence: 99%

Chronic hepatitis C: This and the new era of treatment

Bertino

Ardiri

Proiti

et al. 2016

WJH

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Over the last years it has started a real revolution in the treatment of chronic hepatitis C. This occurred for the availability of direct-acting antiviral agents that allow to reach sustained virologic response in approximately 90% of cases. In the near future further progress will be achieved with the use of pan-genotypic drugs with high efficacy but without side effects. Core tip: This review analyzes the current therapies for chronic hepatitis C and the future challenges of the research. So it tries to give an update on the research of hepatitis C virus (HCV) infection, providing a critical view of the emerging therapies and their impact on the future management of HCV infection. Since novel TOPIC HIGHLIGHT Chronic hepatitis C: This and the new era of treatment2016 Hepatitis C Virus: Global view treatments for HCV infection are highly efficacious but costly, priority should be given to patients with advanced hepatic fibrosis, which is a disease that cannot be deferred. INTRODUCTIONThe hepatitis C virus (HCV), identified in the 70s but cloned in 1989, is a single-stranded RNA virus belonging to the family Flaviviridae.HCV is the main cause of progressive liver diseases and a public health problem worldwide. It is estimated that approximately 150-180 million people in the world are living with chronic hepatitis [1,2] , 350 million of whom die each year from liver damage associated with the infection [3] . About 80% of people infected with HCV develop chronic hepatitis, of which 20%-40% will develop liver cirrhosis or hepatocellular carcinoma (HCC) 20-30 years after infection.As a consequence, chronic HCV infection is the major reason of liver transplantation in developed countries [4][5][6][7] . According to the Global Burden Disease Study in Europe, the death rate for viral hepatitis is significantly higher than that for human immunodeficiency virus (HIV) and acquired immune deficiency syndrome; in particular in 2010, the number of deaths from viral hepatitis have been ten times bigger than that attributed to HIV. It is reasonable to think that this difference is due to the lack of effective therapies for HCV until a few years ago [8] .HCV is also one of the main causes of death [9] . The virus causes both liver damage and extra-hepatic manifestations, many of these syndromes are associated with the ability of HCV to replicate in peripheral blood mononuclear cells (PBMCs); an example is the mixed cryoglobulinemia, which is by far the most common extrahepatic disease closely connected with the infection.Recently it was shown that antiviral treatment is associated with improved renal and cardiovascular outcomes in patients with cryoglobulinemia [4,6,10,11] . Newly approved oral anti-HCV drugs are very safe and effective, but unfortunately their cost will force to choose a priority of treatment. The intent should therefore be to identify and treat patients with a higher risk of morbidity and mortality due to HCV.The availability of these new oral treatments can definitely heal patients and ...

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confidence: 99%

Chronic hepatitis C: This and the new era of treatment

Bertino

Ardiri

Proiti

et al. 2016

WJH

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“…PK studies in mice, rats, and dogs revealed that 88d demonstrated relatively high plasma levels ( C max ), a long half-life, and good oral bioavailability, which was 65% in rats, relative to 11% for 88a . Moreover, 88d was not associated with any significant pathological or clinical observations in rats and dogs during safety, pharmacology, and subchronic toxicity studies …”

Section: Bioisosteric Replacement Of Biphenyl Systemsmentioning

confidence: 99%

Bioisosteres of the Phenyl Ring: Recent Strategic Applications in Lead Optimization and Drug Design

2021

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The benzene moiety is the most prevalent ring system in marketed drugs, underscoring its historic popularity in drug design either as a pharmacophore or as a scaffold that projects pharmacophoric elements. However, introspective analyses of medicinal chemistry practices at the beginning of the 21st century highlighted the indiscriminate deployment of phenyl rings as an important contributor to the poor physicochemical properties of advanced molecules, which limited their prospects of being developed into effective drugs. This Perspective deliberates on the design and applications of bioisosteric replacements for a phenyl ring that have provided practical solutions to a range of developability problems frequently encountered in lead optimization campaigns. While the effect of phenyl ring replacements on compound properties is contextual in nature, bioisosteric substitution can lead to enhanced potency, solubility, and metabolic stability while reducing lipophilicity, plasma protein binding, phospholipidosis potential, and inhibition of cytochrome P450 enzymes and the hERG channel.

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“…This is a period often discussed as one of intense migration and nomadism, while the economy is considered to have been based on pastoralism. The Early Bronze Age Yamnaya period spans from 3300 to 2500 cal BCE and is distributed over a vast territory, with regional variation in material culture [26]. The subsistence economy was based primarily on pastoralism-with some scholars suggesting these populations were highly mobile or semi-nomadic [27]-alongside some initial cultivation of wheat, barley, hemp, millet [28].…”

Section: Cultural Backgroundmentioning

confidence: 99%

Re-evaluating Scythian lifeways: Isotopic analysis of diet and mobility in Iron Age Ukraine

Miller

Johnson

Makhortykh³

et al. 2021

PLoS ONE

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The Scythians are frequently presented, in popular and academic thought alike, as highly mobile warrior nomads who posed a great economic risk to growing Mediterranean empires from the Iron Age into the Classical period. Archaeological studies provide evidence of first millennium BCE urbanism in the steppe while historical texts reference steppe agriculture, challenging traditional characterizations of Scythians as nomads. However, there have been few direct studies of the diet and mobility of populations living in the Pontic steppe and forest-steppe during the Scythian era. Here, we analyse strontium, oxygen, and carbon isotope data from human tooth enamel samples, as well as nitrogen and carbon isotope data of bone collagen, at several Iron Age sites across Ukraine commonly associated with ‘Scythian’ era communities. Our multi-isotopic approach demonstrates generally low levels of human mobility in the vicinity of urban locales, where populations engaged in agro-pastoralism focused primarily on millet agriculture. Some individuals show evidence for long-distance mobility, likely associated with significant inter-regional connections. We argue that this pattern supports economic diversity of urban locales and complex trading networks, rather than a homogeneous nomadic population.

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Discovery of Novel Highly Potent Hepatitis C Virus NS5A Inhibitor (AV4025)

Cited by 15 publications

References 34 publications

Chronic hepatitis C: This and the new era of treatment

Chronic hepatitis C: This and the new era of treatment

Bioisosteres of the Phenyl Ring: Recent Strategic Applications in Lead Optimization and Drug Design

Re-evaluating Scythian lifeways: Isotopic analysis of diet and mobility in Iron Age Ukraine

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