共查询到20条相似文献,搜索用时 15 毫秒
1.
Kumar DV Rai R Brameld KA Somoza JR Rajagopalan R Janc JW Xia YM Ton TL Shaghafi MB Hu H Lehoux I To N Young WB Green MJ 《Bioorganic & medicinal chemistry letters》2011,21(1):82-87
Hepatitis C virus (HCV) infection is treated with a combination of peginterferon alfa-2a/b and ribavirin. To address the limitations of this therapy, numerous small molecule agents are in development, which act by directly affecting key steps in the viral life-cycle. Herein we describe our discovery of quinolone derivatives, novel small-molecules that inhibit NS5b polymerase, a key enzyme of the viral life-cycle. A crystal structure of a quinoline analog bound to NS5B reveals that this class of compounds binds to allosteric site-II (non-nucleoside inhibitor-site 2, NNI-2) of this protein. 相似文献
2.
Kyle Parcella Andrew Nickel Brett R. Beno Steven Sheriff Changhong Wan Ying-Kai Wang Susan B. Roberts Nicholas A. Meanwell John F. Kadow 《Bioorganic & medicinal chemistry letters》2017,27(2):295-298
Alkoxyanthranilic acid derivatives have been identified to inhibit HCV NS5B polymerase, binding in an allosteric site located at the convergence of the palm and thumb regions. Information from co-crystal structures guided the structural design strategy. Ultimately, two independent structural modifications led to a similar shift in binding mode that when combined led to a synergistic improvement in potency and the identification of inhibitors with sub-micromolar HCV NS5B binding potency. 相似文献
3.
Timothy A. Stammers René Coulombe Jean Rancourt Bounkham Thavonekham Gulrez Fazal Sylvie Goulet Araz Jakalian Dominic Wernic Youla Tsantrizos Marc-André Poupart Michael Bös Ginette McKercher Louise Thauvette George Kukolj Pierre L. Beaulieu 《Bioorganic & medicinal chemistry letters》2013,23(9):2585-2589
A novel series of non-nucleoside thumb pocket 2 HCV NS5B polymerase inhibitors were derived from a fragment-based approach using information from X-ray crystallographic analysis of NS5B-inhibitor complexes and iterative rounds of parallel synthesis. Structure-based drug design strategies led to the discovery of potent sub-micromolar inhibitors 11a–c and 12a–c from a weak-binding fragment-like structure 1 as a starting point. 相似文献
4.
Min Zhong Eric Peng Ningwu Huang Qi Huang Anja Huq Meiyen Lau Richard Colonno Leping Li 《Bioorganic & medicinal chemistry letters》2018,28(5):963-968
This letter describes the discovery of a fused benzofuran scaffold viable for preparing a series of novel potent HCV NS5B polymerase non-nucleoside inhibitors. Designed on the basis of the functionalized benzofuran derivative nesbuvir (HCV-796), these compounds presumably bind similarly to the allosteric binding site in the “palm” domain of HCV NS5B protein. SAR of each potential hydrogen-bonding interaction site of this novel scaffold is discussed along with some preliminary genotypic profile and PK data of several advanced compounds. 相似文献
5.
Frank Ruebsam Douglas E. Murphy Chinh V. Tran Lian-Sheng Li Jingjing Zhao Peter S. Dragovich Helen M. McGuire Alan X. Xiang Zhongxiang Sun Benjamin K. Ayida Julie K. Blazel Sun Hee Kim Yuefen Zhou Qing Han Charles R. Kissinger Stephen E. Webber Richard E. Showalter Amit M. Shah Mei Tsan Rupal A. Patel Leo Kirkovsky 《Bioorganic & medicinal chemistry letters》2009,19(22):6404-6412
A novel series of non-nucleoside small molecules containing a tricyclic dihydropyridinone structural motif was identified as potent HCV NS5B polymerase inhibitors. Driven by structure-based design and building on our previous efforts in related series of molecules, we undertook extensive SAR studies, in which we identified a number of metabolically stable and very potent compounds in genotype 1a and 1b replicon assays. This work culminated in the discovery of several inhibitors, which combined potent in vitro antiviral activity against both 1a and 1b genotypes, metabolic stability, good oral bioavailability, and high C12 (PO)/EC50 ratios. 相似文献
6.
Moyi Liu Qiaoling Xu Su Guo Ruixi Zuo Yue Hong Yong Luo Yingxiu Li Ping Gong Yajing Liu 《Bioorganic & medicinal chemistry》2018,26(9):2621-2631
The hepatitis C virus (HCV) NS5B polymerase is an attractive target for the development of novel and selective inhibitors of HCV replication. In this paper, the design, synthesis, and preliminary SAR studies of novel inhibitors of HCV NS5B polymerase based on the structure of tegobuvir have been described. The efforts to optimize the antiviral potency and reduce the treatment side effects with respect to genotype 1b resulted in the discovery of compound 3, which exhibited an EC50 of 1.163?nM and a CC50 >200?nM in a cell-based HCV replicon system assay. Additionally, testing for inhibition of the hERG channel showed a marked improvement over tegobuvir and the pharmacokinetic properties of compound 3 indicated that it was worthy of further investigation as a non-nucleoside inhibitor of HCV NS5B polymerase. 相似文献
7.
Hutchinson DK Flentge CA Donner PL Wagner R Maring CJ Kati WM Liu Y Masse SV Middleton T Mo H Montgomery D Jiang WW Koev G Beno DW Stewart KD Stoll VS Molla A Kempf DJ 《Bioorganic & medicinal chemistry letters》2011,21(6):1876-1879
A series of quinoline derivatives was synthesized as potential bioisosteric replacements for the benzothiadiazine moiety of earlier Hepatitis C NS5B polymerase inhibitors. Several of these compounds exhibited potent activity in enzymatic and replicon assays. 相似文献
8.
《Bioorganic & medicinal chemistry letters》2014,24(10):2288-2294
Two novel series of spirocyclic piperidine analogs appended to a pyrazolo[1,5-a]pyridine core were designed, synthesized and evaluated for their anti-HCV activity. A series of piperidine ketals afforded dispiro 6p which showed excellent in vitro anti-HCV activities (EC50 of 1.5 nM and 1.2 nM against genotype 1a and 1b replicons, respectively). A series of piperidine oxazolidinones afforded 27c which showed EC50’s of 10.9 nM and 6.1 nM against 1a and 1b replicons, respectively. Both compounds 6p and 27c bound directly to non-structural NS4B protein in vitro (IC50’s = 10.2 and 30.4 nM, respectively) and exhibited reduced potency in replicons containing resistance mutations encoding changes in the NS4B protein. 相似文献
9.
A. Chris Krueger John T. Randolph David A. DeGoey Pamela L. Donner Charles A. Flentge Douglas K. Hutchinson Dachun Liu Christopher E. Motter Todd W. Rockway Rolf Wagner David W.A. Beno Gennadiy Koev Hock B. Lim Jill M. Beyer Rubina Mondal Yaya Liu Warren M. Kati Kenton L. Longenecker Clarence J. Maring 《Bioorganic & medicinal chemistry letters》2013,23(12):3487-3490
The synthesis and structure–activity relationships of a novel aryl uracil series which contains a fused 5,6-bicyclic ring unit for HCV NS5B inhibition is described. Several analogs display replicon cell culture potencies in the low nanomolar range along with excellent rat pharmacokinetic values. 相似文献
10.
Interference of HCV replication by cell penetrable human monoclonal scFv specific to NS5B polymerase
《MABS-AUSTIN》2013,5(5):1327-1339
A new class of hepatitis C virus (HCV)-targeted therapeutics that is safe, broadly effective and can cope with virus mutations is needed. The HCV's NS5B is highly conserved and different from human protein, and thus it is an attractive target for anti-HCV therapeutics development. In this study, NS5B bound-phage clones selected from a human single chain variable antibody fragment (scFv) phage display library were used to transform appropriate E. coli bacteria. Two scFv inhibiting HCV polymerase activity were selected. The scFvs were linked to a cell penetrating peptide to make cell penetrable scFvs. The transbodies reduced the HCV RNA and infectious virus particles released into the culture medium and inside hepatic cells transfected with a heterologous HCV replicon. They also rescued the innate immune response of the transfected cells. Phage mimotope search and homology modeling/molecular docking revealed the NS5B subdomains and residues bound by the scFvs. The scFv mimotopes matched residues of the NS5B, which are important for nucleolin binding during HCV replication, as well as residues that interconnect the fingers and thumb domains for forming a polymerase active groove. Both scFvs docked on several residues at the thumb armadillo-like fold that could be the polymerase interactive sites of other viral/host proteins for the formation of the replication complex and replication initiation. In conclusion, human transbodies that inhibited HCV RdRp activity and HCV replication and restored the host innate immune response were produced. They are potentially future interferon-free anti-HCV candidates, particularly in combination with other cognates that are specific to NS5B epitopes and other HCV enzymes. 相似文献
11.
Interference of HCV replication by cell penetrable human monoclonal scFv specific to NS5B polymerase
Kanyarat Thueng-in Jeeraphong Thanongsaksrikul Surasak Jittavisutthikul Watee Seesuay Monrat Chulanetra Yuwaporn Sakolvaree Potjanee Srimanote Wanpen Chaicumpa 《MABS-AUSTIN》2014,6(5):1327-1339
A new class of hepatitis C virus (HCV)-targeted therapeutics that is safe, broadly effective and can cope with virus mutations is needed. The HCV''s NS5B is highly conserved and different from human protein, and thus it is an attractive target for anti-HCV therapeutics development. In this study, NS5B bound-phage clones selected from a human single chain variable antibody fragment (scFv) phage display library were used to transform appropriate E. coli bacteria. Two scFv inhibiting HCV polymerase activity were selected. The scFvs were linked to a cell penetrating peptide to make cell penetrable scFvs. The transbodies reduced the HCV RNA and infectious virus particles released into the culture medium and inside hepatic cells transfected with a heterologous HCV replicon. They also rescued the innate immune response of the transfected cells. Phage mimotope search and homology modeling/molecular docking revealed the NS5B subdomains and residues bound by the scFvs. The scFv mimotopes matched residues of the NS5B, which are important for nucleolin binding during HCV replication, as well as residues that interconnect the fingers and thumb domains for forming a polymerase active groove. Both scFvs docked on several residues at the thumb armadillo-like fold that could be the polymerase interactive sites of other viral/host proteins for the formation of the replication complex and replication initiation. In conclusion, human transbodies that inhibited HCV RdRp activity and HCV replication and restored the host innate immune response were produced. They are potentially future interferon-free anti-HCV candidates, particularly in combination with other cognates that are specific to NS5B epitopes and other HCV enzymes. 相似文献
12.
Qingbei Zeng Anilkumar G. Nair Stuart B. Rosenblum Hsueh-Cheng Huang Charles A. Lesburg Yueheng Jiang Oleg Selyutin Tin-Yau Chan Frank Bennett Kevin X. Chen Srikanth Venkatraman Mousumi Sannigrahi Francisco Velazquez Jose S. Duca Stephen Gavalas Yuhua Huang Haiyan Pu Li Wang Joseph A. Kozlowski 《Bioorganic & medicinal chemistry letters》2013,23(24):6585-6587
The discovery of lead compound 2e was described. Its covalent binding to HCV NS5B polymerase enzyme was investigated by X-ray analysis. The results of distribution, metabolism and pharmacokinetics were reported. Compound 2e was demonstrated to be potent (replicon GT-1b EC50 = 0.003 μM), highly selective, and safe in in vitro and in vivo assays. 相似文献
13.
Bhargav A. Patel Ramalingam Krishnan Nikhil Khadtare K.R. Gurukumar Amartya Basu Payal Arora Aaditya Bhatt Maulik R. Patel Dibyendu Dana Sanjai Kumar Neerja Kaushik-Basu Tanaji T. Talele 《Bioorganic & medicinal chemistry》2013,21(11):3262-3271
Hepatitis C virus (HCV) NS5B polymerase is a key target for anti-HCV therapeutics development. Herein, we report the synthesis and in vitro evaluation of anti-NS5B polymerase activity of a molecular hybrid of our previously reported lead compounds 1 (IC50 = 7.7 μM) and 2 (IC50 = 10.6 μM) as represented by hybrid compound 27 (IC50 = 6.7 μM). We have explored the optimal substituents on the terminal phenyl ring of the 3-phenoxybenzylidene moiety in 27, by generating a set of six analogs. This resulted in the identification of compound 34 with an IC50 of 2.6 μM. To probe the role of stereochemistry towards the observed biological activity, we synthesized and evaluated the d-isomers 41 (IC50 = 19.3 μM) and 45 (IC50 = 5.4 μM) as enantiomers of the l-isomers 27 and 34, respectively. The binding site of compounds 32 and 34 was mapped to palm pocket-I (PP-I) of NS5B. The docking models of 34 and 45 within the PP-I of NS5B were investigated to envisage the molecular mechanism of inhibition. 相似文献
14.
《Bioorganic & medicinal chemistry letters》2020,30(7):127004
In a lead optimization effort towards NS5B NNI inhibitors, two multi-step parallel libraries were designed and successfully synthesized. Through this effort we discovered compound 9B, which achieved rigorous and delicate balance of inhibition across the common genotypes and mutants with <10 nM potency. In addition, the bicyclic compounds 9B exhibited improved FASSIF solubility over the tetracyclic compound MK-8876. This strategic approach demonstrated that, even within limited reaction scope, multi-step parallel libraries could provide access to more complex chemical space. This expedient access facilitates diverse, purpose-driven optimization of SAR and physicochemical properties. 相似文献
15.
Pierre L. Beaulieu René Coulombe Jianmin Duan Gulrez Fazal Cédrickx Godbout Oliver Hucke Araz Jakalian Marc-André Joly Olivier Lepage Montse Llinàs-Brunet Julie Naud Martin Poirier Nathalie Rioux Bounkham Thavonekham George Kukolj Timothy A. Stammers 《Bioorganic & medicinal chemistry letters》2013,23(14):4132-4140
We describe the structure-based design of a novel lead chemotype that binds to thumb pocket 2 of HCV NS5B polymerase and inhibits cell-based gt1 subgenomic reporter replicons at sub-micromolar concentrations (EC50 <200 nM). This new class of potent thumb pocket 2 inhibitors features a 1H-quinazolin-4-one scaffold derived from hybridization of a previously reported, low affinity thiazolone chemotype with our recently described anthranilic acid series. Guided by X-ray structural information, a key NS5B–ligand interaction involving the carboxylate group of anthranilic acid based inhibitors was replaced by a neutral two-point hydrogen bonding interaction between the quinazolinone scaffold and the protein backbone. The in vitro ADME and in vivo rat PK profile of representative analogs are also presented and provide areas for future optimization of this new class of HCV polymerase inhibitors. 相似文献
16.
Timothy A. Stammers René Coulombe Martin Duplessis Gulrez Fazal Alexandre Gagnon Michel Garneau Sylvie Goulet Araz Jakalian Steven LaPlante Jean Rancourt Bounkham Thavonekham Dominik Wernic George Kukolj Pierre L. Beaulieu 《Bioorganic & medicinal chemistry letters》2013,23(24):6879-6885
Optimization efforts on the anthranilic acid-based Thumb Pocket 2 HCV NS5B polymerase inhibitors 1 and 2 resulted in the identification of multiple structural elements that contributed to improved cell culture potency. The additive effect of these elements resulted in compound 46, an inhibitor with enzymatic (IC50) and cell culture (EC50) potencies of less than 100 nanomolar. 相似文献
17.
I. Novel HCV NS5B polymerase inhibitors: discovery of indole 2-carboxylic acids with C3-heterocycles
Anilkumar GN Lesburg CA Selyutin O Rosenblum SB Zeng Q Jiang Y Chan TY Pu H Vaccaro H Wang L Bennett F Chen KX Duca J Gavalas S Huang Y Pinto P Sannigrahi M Velazquez F Venkatraman S Vibulbhan B Agrawal S Butkiewicz N Feld B Ferrari E He Z Jiang CK Palermo RE McMonagle P Huang HC Shih NY Njoroge G Kozlowski JA 《Bioorganic & medicinal chemistry letters》2011,21(18):5336-5341
SAR development of indole-based palm site inhibitors of HCV NS5B polymerase exemplified by initial indole lead 1 (NS5B IC(50)=0.9 μM, replicon EC(50)>100 μM) is described. Structure-based drug design led to the incorporation of novel heterocyclic moieties at the indole C3-position which formed a bidentate interaction with the protein backbone. SAR development resulted in leads 7q (NS5B IC(50)=0.032 μM, replicon EC(50)=1.4 μM) and 7r (NS5B IC(50)=0.017 μM, replicon EC(50)=0.3 μM) with improved enzyme and replicon activity. 相似文献
18.
Beaulieu PL Chabot C Duan J Garneau M Gillard J Jolicoeur E Poirier M Poupart MA Stammers TA Kukolj G Tsantrizos YS 《Bioorganic & medicinal chemistry letters》2011,21(12):3664-3670
In this part 2, new indole 5-carboxamide Thumb Pocket 1 inhibitors of HCV NS5B polymerase are described. Structure-activity relationships (SAR) were explored at the central amino acid linker position and the right-hand-side of the molecule in an attempt to identify molecules with a balanced overall profile of potency (EC50 <100 nM), physicochemical properties and ADME characteristics. 相似文献
19.
Prasanthi Polamreddy Premkumar Arumugam Raghu Bheemanati Poornima Esram Manoj Kumar Mahto 《Journal of biomolecular structure & dynamics》2020,38(5):1448-1466
AbstractNonstructural protein 5B (NS5B), the RNA-dependent RNA polymerase of Hepatitis C Virus (HCV), plays a key role in viral amplification and is an attractive and most explored target for discovery of new therapeutic agents for Hepatitis C. Though safe and effective, NS5B inhibitors were launched in 2013 (Sovaldi) and 2014 (Harvoni, Viekira Pak), the high price tags of these medications limit their use among poor people in developing countries. Hence, still there exists a need for cost-effective and short duration anti-HCV agents especially those targeting niche patient population who were non-respondent to earlier therapies or with comorbid conditions. The present study describes the discovery of novel non-nucleoside (NNI) inhibitors of NS5B using a series of rational drug design techniques such as virtual screening, scaffold matching and molecular docking. 2D and 3D structure based virtual screening technique identified 300 hit compounds. Top 20 hits were screened out from identified hits using molecular docking technique. Four molecules, that are representative of 20 hits were evaluated for binding affinity under in vitro conditions using surface plasmon resonance-based assay and the results emphasized that compound with CoCoCo ID: 412075 could exhibit good binding response toward NS5B and could be a potential candidate as NS5B inhibitor.Communicated by Ramaswamy H. Sarma 相似文献
20.
《Bioorganic & medicinal chemistry letters》2014,24(14):3092-3095
The first synthesis of 1′-cyano-2′-C-methyl pyrimidine nucleosides is described. Anti-HCV activity of these nucleosides and their nucleotide phosphoramidate prodrugs was assessed and compared to the 1′-unsubstituted counterparts and to the related 1′-cyano-2′-C-methyl C-nucleoside parent of GS-6620. 相似文献