Discovery of Novel Urea-Based Hepatitis C Protease Inhibitors with High Potency against Protease-Inhibitor-Resistant Mutants

Kazmierski, Wieslaw M.; Hamatake, Robert; Duan, Maosheng; Wright, Laura; Smith, Gary K.; Jarvest, Richard L.; Ji, Jingjing; Cooper, Joel P.; Tallant, Matthew D.; Crosby, Renae M.; Creech, Katrina L.; Wang, Amy; Li, Xianfeng; Zhang, Suoming; Zhang, Yongkang; Liu, Yang; Ding, Charles Z.; Zhou, Yasheen; Plattner, Jacob J.; Baker, Stephen J.; Bu, Wei; Liu, Liang

doi:10.1021/jm201278q

Cited by 35 publications

(23 citation statements)

References 22 publications

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“…As they determine successful viral replication, Mpro and PLpro became potential drug targets [9][10][11]. Inhibition of viral proteases crucial for polypeptide processing has been reported as a successful strategy for the treatment of other viruses-hepatitis C virus (HCV) and human immunodeficiency virus (HIV) [12,13].…”

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 Papain-Like Protease Potential Inhibitors—In Silico Quantitative Assessment

Stasiulewicz

Maksymiuk

Nguyen

et al. 2021

IJMS

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encodes the papain-like protease (PLpro). The protein not only plays an essential role in viral replication but also cleaves ubiquitin and ubiquitin-like interferon-stimulated gene 15 protein (ISG15) from host proteins, making it an important target for developing new antiviral drugs. In this study, we searched for novel, noncovalent potential PLpro inhibitors by employing a multistep in silico screening of a 15 million compound library. The selectivity of the best-scored compounds was evaluated by checking their binding affinity to the human ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), which, as a deubiquitylating enzyme, exhibits structural and functional similarities to the PLpro. As a result, we identified 387 potential, selective PLpro inhibitors, from which we retrieved the 20 best compounds according to their IC50 values toward PLpro estimated by a multiple linear regression model. The selected candidates display potential activity against the protein with IC50 values in the nanomolar range from approximately 159 to 505 nM and mostly adopt a similar binding mode to the known, noncovalent SARS-CoV-2 PLpro inhibitors. We further propose the six most promising compounds for future in vitro evaluation. The results for the top potential PLpro inhibitors are deposited in the database prepared to facilitate research on anti-SARS-CoV-2 drugs.

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Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 Papain-Like Protease Potential Inhibitors—In Silico Quantitative Assessment

Stasiulewicz

Maksymiuk

Nguyen

et al. 2021

IJMS

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“…Understanding of flavivirus proteins and other RNA viruses has benefited from the EU funded project VIZIER 77 , in particular several West Nile virus, dengue virus and other flavivirus structures of NS3 or NS5 were solved during this project and allosteric inhibitor sites were identified on NS5 78 . Multiple pharmaceutical companies have worked on this target for HCV leading to clinical candidates like IDX320 79 , danoprevir (ITMN-191/R7227) 80 , GS-9256 81 and others 82 , 83 . The only HCV protease targeting FDA approved drug is simeprevir, TMC435 84 , 85 and its use is avoided in pregnancy.…”

Section: Discussionmentioning

confidence: 99%

Illustrating and homology modeling the proteins of the Zika virus

Ekins

John²,

Neves

et al. 2016

F1000Res

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The Zika virus (ZIKV) is a flavivirus of the family Flaviviridae, which is similar to dengue virus, yellow fever and West Nile virus. Recent outbreaks in South America, Latin America, the Caribbean and in particular Brazil have led to concern for the spread of the disease and potential to cause Guillain-Barré syndrome and microcephaly. Although ZIKV has been known of for over 60 years there is very little in the way of knowledge of the virus with few publications and no crystal structures. No antivirals have been tested against it either in vitro or in vivo. ZIKV therefore epitomizes a neglected disease. Several suggested steps have been proposed which could be taken to initiate ZIKV antiviral drug discovery using both high throughput screens as well as structure-based design based on homology models for the key proteins. We now describe preliminary homology models created for NS5, FtsJ, NS4B, NS4A, HELICc, DEXDc, peptidase S7, NS2B, NS2A, NS1, E stem, glycoprotein M, propeptide, capsid and glycoprotein E using SWISS-MODEL. Eleven out of 15 models pass our model quality criteria for their further use. While a ZIKV glycoprotein E homology model was initially described in the immature conformation as a trimer, we now describe the mature dimer conformer which allowed the construction of an illustration of the complete virion. By comparing illustrations of ZIKV based on this new homology model and the dengue virus crystal structure we propose potential differences that could be exploited for antiviral and vaccine design. The prediction of sites for glycosylation on this protein may also be useful in this regard. While we await a cryo-EM structure of ZIKV and eventual crystal structures of the individual proteins, these homology models provide the community with a starting point for structure-based design of drugs and vaccines as well as a for computational virtual screening.

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“…Wissenschaftler von GlaxoSmithKline und Anacor Pharmaceuticals Inc. berichteten über die zufällige Entdeckung eines neuartigen potenten HCV‐Protease‐Inhibitors, welcher als Nebenprodukt während der Synthese einer anderen antiviralen Verbindung entsteht [110] . Wie einige der Vorgänger (z.…”

Section: Anwendungen In Der Synthese Aktiver Pharmazeutischer Wirkstounclassified

Durch Nitro‐ und andere elektronenziehende Gruppen aktivierte Ruthenium‐Katalysatoren für die Olefinmetathese

Kajetanowicz¹,

Grela

2020

Angewandte Chemie

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Fortschrittliche Anwendungen der mit dem Nobelpreis ausgezeichneten Olefinmetathese erfordern nutzerfreundliche Handhabung und vielseitig anwendbare Katalysatoren. Unter den zahlreichen bekannten Metathesekatalysatoren, welche zu den zwei Klassen der Schrock‐ und Grubbs‐Katalysatoren gehören, bietet die Untergruppe der chelatisierten Rutheniumbenzyliden‐Komplexe (auch genannt Hoveyda‐Grubbs‐Katalysatoren) durch zusätzliche Aktivierung durch elektronenziehende Gruppen (EWG) eine hochgradig abstimmbare Plattform. Im vorliegenden Aufsatz werden der Ursprung des EWG‐Aktivierungskonzeptes und ausgewählte Anwendungen der resultierenden Katalysatoren in zielgerichteten Synthesen, im Bereich der medizinischen Chemie sowie in der Herstellung von Feinchemikalien und der Materialchemie erörtert. Darauf basierend werden dem Anwender einige Vorschläge hinsichtlich der Minimierung der Katalysatorbeladung, der Selektivitätskontrolle und allgemeine Optimierungshinweise der Olefinmetathese gegeben.

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Discovery of Novel Urea-Based Hepatitis C Protease Inhibitors with High Potency against Protease-Inhibitor-Resistant Mutants

Cited by 35 publications

References 22 publications

SARS-CoV-2 Papain-Like Protease Potential Inhibitors—In Silico Quantitative Assessment

SARS-CoV-2 Papain-Like Protease Potential Inhibitors—In Silico Quantitative Assessment

Illustrating and homology modeling the proteins of the Zika virus

Durch Nitro‐ und andere elektronenziehende Gruppen aktivierte Ruthenium‐Katalysatoren für die Olefinmetathese

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