共查询到20条相似文献,搜索用时 15 毫秒
1.
Kenji Namoto Finton Sirockin Holger Sellner Christian Wiesmann Frederic Villard Robert J. Moreau Eric Valeur Stephanie C. Paulding Simone Schleeger Kathrin Schipp Joachim Loup Lori Andrews Ryann Swale Michael Robinson Christopher J. Farady 《Bioorganic & medicinal chemistry letters》2018,28(5):906-909
The design and synthesis of macrocyclic inhibitors of human rhinovirus 3C protease is described. A macrocyclic linkage of the P1 and P3 residues, and the subsequent structure-based optimization of the macrocycle conformation and size led to the identification of a potent biochemical inhibitor 10 with sub-micromolar antiviral activity. 相似文献
2.
《Bioorganic & medicinal chemistry letters》2014,24(2):490-494
Foot-and-mouth disease virus (FMDV) causes a highly infectious and economically devastating disease of livestock. The FMDV genome is translated as a single polypeptide precursor that is cleaved into functional proteins predominantly by the highly conserved viral 3C protease, making this enzyme an attractive target for antiviral drugs. A peptide corresponding to an optimal substrate has been modified at the C-terminus, by the addition of a warhead, to produce irreversible inhibitors that react as Michael acceptors with the enzyme active site. Further investigation highlighted key structural determinants for inhibition, with a positively charged P2 being particularly important for potency. 相似文献
3.
Venkatraman S Kong J Nimkar S Wang QM Aubé J Hanzlik RP 《Bioorganic & medicinal chemistry letters》1999,9(4):577-580
A series of azapeptides was prepared and assessed as inhibitors of the human rhinovirus 3C protease. Boc-VLFaQ-OPh was a slow-turnover substrate that gave transient (ca. 1-2 h) inhibition as it underwent hydrolysis. Boc-VLFaG-OPh gave very slow but essentially irreversible inhibition. 相似文献
4.
P S Dragovich R Zhou D J Skalitzky S A Fuhrman A K Patick C E Ford J W Meador S T Worland 《Bioorganic & medicinal chemistry》1999,7(4):589-598
The optimization of a series of irreversible human rhinovirus (HRV) 3C protease (3CP) inhibitors is described. These inhibitors are comprised of an L-Leu-L-Phe-L-Gln tripeptide containing an N-terminal amide moiety and a C-terminal ethyl propenoate Michael acceptor. Examination of approximately 500 compounds with varying N-terminal amides utilizing solid-phase synthesis and high-throughput assay techniques is described along with the solution phase preparation of several highly active molecules. A tripeptide Michael acceptor containing an N-terminal amide derived from 5-methylisoxazole-3-carboxylic acid is shown to exhibit potent, irreversible anti-3CP activity (k(obs)/[I] = 260,000 M(-1) s(-1); type-14 3CP) and broad-spectrum antirhinoviral properties (average EC50 = 0.47 microM against four different HRV serotypes). 相似文献
5.
P S Dragovich S E Webber T J Prins R Zhou J T Marakovits J G Tikhe S A Fuhrman A K Patick D A Matthews C E Ford E L Brown S L Binford J W Meador R A Ferre S T Worland 《Bioorganic & medicinal chemistry letters》1999,9(15):2189-2194
Tripeptide-derived molecules incorporating N-methyl amino acid residues and C-terminal Michael acceptor moieties were evaluated as irreversible inhibitors of the cysteine-containing human rhinovirus 3C protease (3CP). Such compounds displayed good 3CP inhibition activity (k(obs)/[I] up to 610,000 M(-1) s(-1)) and potent in vitro antiviral properties (EC50 approaching 0.03 microM) when tested against HRV serotype-14. 相似文献
6.
Baxter A Chambers M Edfeldt F Edman K Freeman A Johansson C King S Morley A Petersen J Rawlins P Spadola L Thong B Van de Poël H Williams N 《Bioorganic & medicinal chemistry letters》2011,21(2):777-780
The first known non-covalent inhibitors of rhinovirus 3C protease (3CP) have been identified through fragment based screening and hit identification activities. 相似文献
7.
Qiyan Zhang Ruiyuan Cao An Liu Shihai Lei Yuexiang Li Jingjing Yang Song Li Junhai Xiao 《Bioorganic & medicinal chemistry letters》2017,27(17):4061-4065
The human rhinovirus (HRV) is the most significant cause of the common cold all over the world. The maturation and replication of this virus entirely depend on the activity of a virus-encoded 3C protease. Due to the high conservation among different serotypes and the minimal homology existing between 3C protease and known mammalian enzymes, 3C protease has been regarded as an attractive target for the treatment of HRV infections. In this study, we identified a novel (4R,5R)-N4-(2-((3-methoxyphenyl)amino)ethyl)-2,2-dimethyl-N5-(naphthalen-2-yl)-1,3-dioxolane-4,5-dicarboxamide (7a) to be a HRV 3C protease inhibitor via virtual screening. Further research has been focused on the design, synthesis and in vitro biological evaluation of 7a derivatives. The studies revealed that compound 7d has an IC50 value of 2.50 ± 0.7 µM against HRV 3C protease, and it thus could serve as a promising compound for the development of novel anti-rhinoviral medicines. 相似文献
8.
Xian M Wang QM Chen X Wang K Wang PG 《Bioorganic & medicinal chemistry letters》2000,10(18):2097-2100
Human rhinovirus (HRV) 3C protease was inactivated by a series of S-nitrosothiols. These compounds exhibited different inhibitory activities in a time- and concentration-dependent manner with second-order rate constants (kinact/K(I)) ranging from 131 to 5360 M(-1) min(-1). The inactive enzyme could be re-activated by DTT, GSH and ascorbate, which indicated the inactivation mechanism was through an S-transnitrosylation process. 相似文献
9.
Dragovich PS Zhou R Webber SE Prins TJ Kwok AK Okano K Fuhrman SA Zalman LS Maldonado FC Brown EL Meador JW Patick AK Ford CE Brothers MA Binford SL Matthews DA Ferre RA Worland ST 《Bioorganic & medicinal chemistry letters》2000,10(1):45-48
Tripeptide-derived molecules incorporating C-terminal ketone electrophiles were evaluated as reversible inhibitors of the cysteine-containing human rhinovirus 3C protease (3CP). An optimized example of such compounds displayed potent 3CP inhibition activity (K = 0.0045 microM) and in vitro antiviral properties (EC50=0.34 microM) when tested against HRV serotype-14. 相似文献
10.
11.
Dragovich PS Prins TJ Zhou R Johnson TO Brown EL Maldonado FC Fuhrman SA Zalman LS Patick AK Matthews DA Hou X Meador JW Ferre RA Worland ST 《Bioorganic & medicinal chemistry letters》2002,12(5):733-738
The structure-based design, chemical synthesis, and biological evaluation of bicyclic 2-pyridone-containing human rhinovirus (HRV) 3C protease (3CP) inhibitors are described. An optimized compound is shown to exhibit antiviral activity when tested against a variety of HRV serotypes (EC(50)'s ranging from 0.037 to 0.162 microM). 相似文献
12.
The expression and purification of human rhinovirus protease 3C 总被引:2,自引:0,他引:2
J A Knott D C Orr D S Montgomery C A Sullivan A Weston 《European journal of biochemistry》1989,182(3):547-555
Human rhinovirus type 14 protease 3C was expressed as a soluble and active protein in Escherichia coli. The protease was purified by a cationic-exchange step followed by gel filtration on a TSK 3000 column. The final yield of purified protease was in the range 0.5-1.0 mg/l culture grown to A550 = 1.0. Sequence analysis revealed that greater than 90% of the N-terminal residues were methionine. The enzyme activity of the purified protease was measured by cleavage of a synthetic peptide representing a predicted Gln/Gly viral polyprotein cleavage site. A mutant protease (Cys146----Ser) was produced and purified in the same way. The yield of mutant protease 3C was approximately 150 micrograms/l from a culture grown to A550 = 1.0. This mutant protease 3C did not cleave the synthetic peptide substrate. 相似文献
13.
Allan M. Prior Yunjeong Kim Sahani Weerasekara Meghan Moroze Kevin R. Alliston Roxanne Adeline Z. Uy William C. Groutas Kyeong-Ok Chang Duy H. Hua 《Bioorganic & medicinal chemistry letters》2013,23(23):6317-6320
A class of tripeptidyl transition state inhibitors containing a P1 glutamine surrogate, a P2 leucine, and a P3 arylalanines, was found to potently inhibit Norwalk virus replication in enzyme and cell based assays. An array of warheads, including aldehyde, α-ketoamide, bisulfite adduct, and α-hydroxyphosphonate transition state mimic, was also investigated. Tripeptidyls 2 and 6 possess antiviral activities against noroviruses, human rhinovirus, severe acute respiratory syndrome coronavirus, and coronavirus 229E, suggesting a broad range of antiviral activities. 相似文献
14.
Tiew KC He G Aravapalli S Mandadapu SR Gunnam MR Alliston KR Lushington GH Kim Y Chang KO Groutas WC 《Bioorganic & medicinal chemistry letters》2011,21(18):5315-5319
The first series of peptidyl aldehyde inhibitors that incorporate in their structure a glutamine surrogate has been designed and synthesized based on the known substrate specificity of Norwalk virus 3C protease. The inhibitory activity of the compounds with the protease and with a norovirus cell-based replicon system was investigated. Members of this class of compounds exhibited noteworthy activity both in vitro and in a cell-based replicon system. 相似文献
15.
Kuo CJ Shie JJ Fang JM Yen GR Hsu JT Liu HG Tseng SN Chang SC Lee CY Shih SR Liang PH 《Bioorganic & medicinal chemistry》2008,16(15):7388-7398
Human enterovirus (EV) belongs to the picornavirus family, which consists of over 200 medically relevant viruses. A peptidomimetic inhibitor AG7088 was developed to inhibit the 3C protease of rhinovirus (a member of the family), a chymotrypsin-like protease required for viral replication, by forming a covalent bond with the active site Cys residue. In this study, we have prepared the recombinant 3C protease from EV71 (TW/2231/98), a particular strain which causes severe outbreaks in Asia, and developed inhibitors against the protease and the viral replication. For inhibitor design, the P3 group of AG7088, which is not interacting with the rhinovirus protease, was replaced with a series of cinnamoyl derivatives directly linked to P2 group through an amide bond to simplify the synthesis. While the replacement caused decreased potency, the activity can be largely improved by substituting the alpha,beta-unsaturated ester with an aldehyde at the P1' position. The best inhibitor 10b showed EC(50) of 18 nM without apparent toxicity (CC(50)>25 microM). Our study provides potent inhibitors of the EV71 3C protease as anti-EV71 agents and facilitates the combinatorial synthesis of derivatives for further improving the inhibitory activity. 相似文献
16.
Substrate requirements of human rhinovirus 3C protease for peptide cleavage in vitro 总被引:20,自引:0,他引:20
M G Cordingley P L Callahan V V Sardana V M Garsky R J Colonno 《The Journal of biological chemistry》1990,265(16):9062-9065
A series of synthetic peptides representing authentic proteolytic cleavage sites of human rhinovirus type 14 were assayed as substrates for purified 3C protease. Competition cleavage assays were employed to determine the relative specificity constants (Kcat/Km) for substrates with sequences related to the viral 2C-3A cleavage site. Variable length peptides representing the 2C-3A cleavage site were cleaved with comparable efficiency. These studies defined a minimum substrate of 6 amino acids (TLFQ/GP), although retention of the residue at position P5 (ETLFQ/GP) resulted in a better substrate by an order of magnitude. Amino acid substitutions at position P5, P4, P1', or P2' indicated that the identity of the residue at position P5 was not critical, whereas substitutions at position P4, P1' or P2' resulted in substrates with Kcat/Km values varying over 2 orders of magnitude. In contrast to the 2C-3A cleavage site, small peptide derivatives representative of the 3A-3B cleavage site were relatively poor substrates, which suggested that residues flanking the minimum core sequence may influence susceptibility to cleavage. The 3C protease of rhinovirus type 14 was also capable of cleaving peptides representing comparable cleavage sites predicted for coxsackie B virus and poliovirus. 相似文献
17.
A series of bicyclic pyrimidinone-based HCV NS3 protease inhibitors was synthesized via selective C8 position functionalization. Substituted phenylamides and phenylureas were preferred in the S2 binding pocket. 相似文献
18.
Zhang X Schmitt AC Jiang W Wasserman Z Decicco CP 《Bioorganic & medicinal chemistry letters》2003,13(6):1157-1160
Starting from a hexapeptide boronic acid lead, 3-amino bicyclic pyrazinones as novel beta-sheet dipeptide mimetics have been designed and synthesized. Side-chain manipulation of this scaffold generated a series of potent, nonpeptidic inhibitors of HCV NS3 protease. 相似文献
19.
Francesco G. Salituro Christopher T. Baker John J. Court David D. Deininger Eunice E. Kim Biquin Li Perry M. Novak Bhisetti G. Rao S. Pazhanisamy Margaret D. Porter Wayne C. Schairer Roger D. Tung 《Bioorganic & medicinal chemistry letters》1998,8(24):955-3642
A set of HIV protease inhibitors represented by compound 2 has previously been described. Structural and conformational analysis of this compound suggested that conformational restriction of the P1/P2 portion of the molecule could lead to a novel set of potent protease inhibitors. Thus, probe compounds 3–7 were designed, synthesized, and found to be potent inhibitors of HIV protease. 相似文献
20.
Slater MJ Andrews DM Baker G Bethell SS Carey S Chaignot H Clarke B Coomber B Ellis M Good A Gray N Hardy G Jones P Mills G Robinson E 《Bioorganic & medicinal chemistry letters》2002,12(23):3359-3362
Using a pyrrolidine-5,5-trans-lactam template, we have designed small, neutral, mechanism-based inhibitors of hepatitis C NS3/4A protease. Compound 11a, with an alpha-ethyl P1 substituent and a Boc-valine substituent at the pyrrolidine nitrogen, has an IC(50)=30 microM. 相似文献