Abstract:
:Disulfide bridges that stabilize the native conformation of conotoxins pose a challenge in the synthesis of smaller conotoxin analogues. Herein we describe the synthesis of a minimized analogue of the analgesic mu-conotoxin KIIIA that blocks two sodium channel subtypes, the neuronal Na(V)1.2 and skeletal muscle Na(V)1.4. Three disulfide-deficient analogues of KIIIA were initially synthesized in which the native disulfide bridge formed between either C1-C9, C2-C15, or C4-C16 was removed. Deletion of the first bridge only slightly affected the peptide's bioactivity. To further minimize this analogue, the N-terminal residue was removed and two nonessential serine residues were replaced by a single 5-amino-3-oxapentanoic acid residue. The resulting "polytide" analogue retained the ability to block sodium channels and to produce analgesia. Until now, the peptidomimetic approach applied to conotoxins has progressed only modestly at best; thus, the disulfide-deficient analogues containing backbone spacers provide an alternative advance toward the development of conopeptide-based therapeutics.
journal_name
ChemMedChemjournal_title
ChemMedChemauthors
Han TS,Zhang MM,Walewska A,Gruszczynski P,Robertson CR,Cheatham TE 3rd,Yoshikami D,Olivera BM,Bulaj Gdoi
10.1002/cmdc.200800292subject
Has Abstractpub_date
2009-03-01 00:00:00pages
406-14issue
3eissn
1860-7179issn
1860-7187journal_volume
4pub_type
杂志文章相关文献
ChemMedChem文献大全abstract::A novel type of oligonucleotide has been developed, characterized by the attachment of a lysyl moiety to a 2'-O-aminohexyl linker. A protected lysine building block was tethered to 2'-O-aminohexyluridine, and the product was converted into the corresponding phosphoramidite. Up to six modified nucleosides were incorpor...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200700169
更新日期:2008-01-01 00:00:00
abstract::Protein disulfide isomerase (PDI) is overexpressed in glioblastoma, the most aggressive form of brain cancer, and folds nascent proteins responsible for the progression and spread of the disease. Herein we describe a novel nanomolar PDI inhibitor, pyrimidotriazinedione 35G8, that is toxic in a panel of human glioblast...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201700629
更新日期:2018-01-22 00:00:00
abstract::Despite improvements in the treatment and prevention of cancer, the number of new diagnoses continues to rise; this has fuelled substantial interest in the development of new and effective chemotherapeutic agents. Compounds of the triazene class, such as dacarbazine, have been used in the clinical management of many c...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201100027
更新日期:2011-07-04 00:00:00
abstract::Abnormally high corticosteroid levels are responsible for the onset of serious hormone-related diseases, and the inhibition of their biosynthesis by targeting cytochrome P450 (CYP) isoforms CYP11B1 and CYP11B2 has emerged as a promising strategy to restore healthy physiological levels of corticosteroids. With the aim ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201600078
更新日期:2016-08-19 00:00:00
abstract::There is an urgent clinical need for imaging of α-synuclein (αSyn) fibrils, the hallmark biomarker for Parkinson's disease, in neurodegenerative disorders. Despite immense efforts, promising tracer candidates for nuclear imaging of αSyn are rare. Diphenyl pyrazoles are known modulators of αSyn aggregation and thus bea...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201900689
更新日期:2020-03-05 00:00:00
abstract::N-Acylethanolamine acid amidase (NAAA) is a cysteine hydrolase that catalyzes the hydrolysis of endogenous lipid mediators such as palmitoylethanolamide (PEA). PEA has been shown to exert anti-inflammatory and antinociceptive effects in animals by engaging peroxisome proliferator-activated receptor α (PPAR-α). Thus, p...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201300546
更新日期:2014-07-01 00:00:00
abstract::The protozoan parasite Plasmodium falciparum causes the most severe and prevailing form of malaria in sub-Saharan Africa. Previously, we identified the plasmodial lactate transporter, PfFNT, a member of the microbial formate-nitrite transporter family, as a novel antimalarial drug target. With the pentafluoro-3-hydrox...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.202000952
更新日期:2020-12-18 00:00:00
abstract::Despite bioavailability issues, tea catechins have emerged as promising chemopreventive agents because of their efficacy in various animal models. We synthesized two catechin-derived compounds, 3-O-(3,4,5-trimethoxybenzoyl)-(-)-catechin (TMCG) and 3-O-(3,4,5-trimethoxybenzoyl)-(-)-epicatechin (TMECG), in an attempt to...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201000482
更新日期:2011-03-07 00:00:00
abstract::A common issue during drug design and development is the discovery of novel scaffolds for protein targets. On the one hand the chemical space of purchasable compounds is rather limited; on the other hand artificially generated molecules suffer from a grave lack of accessibility in practice. Therefore, we generated a n...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201700689
更新日期:2018-03-20 00:00:00
abstract::Herein we report the synthesis, photophysical properties, positron emission tomography (PET) imaging and photodynamic therapy (PDT) efficacy of methyl 3-(1'-m-iodobenzyloxy)ethyl-3-devinyl-verdin 4 (with or without the 124 I isotope). The PET imaging ability and ex vivo biodistribution of [124 I]4 were compared with t...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201900352
更新日期:2019-08-20 00:00:00
abstract::A synthetic concept is presented that allows the construction of peptide isostere libraries through polymer-supported C-acylation reactions. A phosphorane linker reagent is used as a carbanion equivalent; by employing MSNT as a coupling reagent, the C-acylation can be conducted without racemization. Diastereoselective...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200500027
更新日期:2006-04-01 00:00:00
abstract::The potassium channel openers flupirtine and retigabine have proven to be valuable analgesics or antiepileptics. Their recent withdrawal due to occasional hepatotoxicity and tissue discoloration, respectively, leaves a therapeutic niche unfilled. Metabolic oxidation of both drugs gives rise to the formation of electro...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201900112
更新日期:2019-05-06 00:00:00
abstract::Modern organizations conducting drug-discovery programs frequently apply high-throughput screening to generate novel hit structures for the indications of interest. Systematic hit-to-lead processes have been established at most pharmaceutical companies to ensure a smooth conversion of hits into high-quality lead struc...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200500031
更新日期:2006-01-01 00:00:00
abstract::Up to 45 % of deaths in developed nations can be attributed to chronic fibroproliferative diseases, highlighting the need for effective therapies. The RGD (Arg-Gly-Asp) integrin αvβ1 was recently investigated for its role in fibrotic disease, and thus warrants therapeutic targeting. Herein we describe the identificati...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201900359
更新日期:2019-07-17 00:00:00
abstract::A series of deuterated curcuminoids (CUR) were synthesized, bearing two to six OCD3 groups, in some cases in combination with methoxy groups, and in others together with fluorine or chlorine atoms. A model ring-deuterated hexamethoxy-CUR-BF2 and its corresponding CUR compound were also synthesized from a 2,4,6-trimeth...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201900179
更新日期:2019-06-18 00:00:00
abstract::Herbal medicines (HMs) are an important source of drugs. In this study, an efficient strategy integrating ultrafiltration LC-MS, microplate bioassays, and molecular docking was proposed to screen high-potency enzyme inhibitors from HMs. Using this strategy, the structure-activity relationships (SARs) including binding...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201600489
更新日期:2016-12-06 00:00:00
abstract::A structure-activity relationship around the amine group of the ambruticin VS series has been developed for antifungal activity. It was shown that the amine can be alkylated through reductive amination without loss of potency. However, if it is converted into either an amide, carbamate, or urea, a significant loss of ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200800008
更新日期:2008-06-01 00:00:00
abstract::Progesterone plays an important role in the female reproductive system. However, there is also evidence that gynecologic disorders/diseases such as uterine fibroids and endometriosis are progesterone-dependent. Steroidal and non-steroidal selective progesterone receptor modulators (SPRMs) have shown potential for the ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201800487
更新日期:2018-11-06 00:00:00
abstract::Iridium(III) complexes of the type [Ir(η(5) -C5 Me5 )Cl2 {Ph2 PCH2 CH2 CH2 S(O)x Ph-κP}] (x=0-2; 1-3) and [Ir(η(5) -C5 Me5 )Cl{Ph2 PCH2 CH2 CH2 S(O)x Ph-κP,κS}][PF6 ] (x=0-1; 4 and 5) with 3-(diphenylphosphino)propyl phenyl sulfide, sulfoxide, and sulfone ligands Ph2 PCH2 CH2 CH2 S(O)x Ph were designed, synthesized, a...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201300479
更新日期:2014-07-01 00:00:00
abstract::The emergence and dissemination of multidrug resistant (MDR) pathogens resistant to nearly all available antibiotics poses a significant threat in clinical therapy. Among them, Klebsiella pneumoniae clinical isolates overexpressing KPC-2 carbapenemase are the most worrisome, extending bacterial resistance to last-reso...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201700788
更新日期:2018-04-06 00:00:00
abstract::The glucocorticoid receptor (GR) is a member of the nuclear receptor superfamily that affects immune response, development, and metabolism in target tissues. Glucocorticoids are widely used to treat diverse pathophysiological conditions, but their clinical applicability is limited by side effects. A prediction of the ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200800274
更新日期:2009-01-01 00:00:00
abstract::The NLRP3 inflammasome is an important regulator of the sterile inflammatory response, and its activation by host-derived sterile molecules leads to the intracellular activation of caspase-1, processing of the pro-inflammatory cytokines interleukin-1β (IL-1β)/IL-18, and pyroptotic cell death. Inappropriate activation ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201700731
更新日期:2018-02-20 00:00:00
abstract::A new class of imidazo[2,1-b]thiazole chalcone derivatives were synthesized and evaluated for their anticancer activity. These chalcone derivatives show promising activity, with log GI(50) values ranging from -7.51 to -4.00. The detailed biological aspects of these derivatives toward the MCF-7 cell line were studied. ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201000346
更新日期:2010-11-08 00:00:00
abstract::A library of 40,000 compounds was screened for inhibitors of 2-methylerythritol 2,4-cyclodiphosphate synthase (IspF) protein from Arabidopsis thaliana using a photometric assay. A thiazolopyrimidine derivative resulting from the high-throughput screen was found to inhibit the IspF proteins of Mycobacterium tuberculosi...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201000083
更新日期:2010-07-05 00:00:00
abstract::LSD1 is a lysine demethylase highly involved in initiation and development of cancer. To design highly effective covalent inhibitors, a strategy is to fill its large catalytic cleft by designing tranylcypromine (TCP) analogs decorated with long, hindered substituents. We prepared three series of TCP analogs, carrying ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201900730
更新日期:2020-04-03 00:00:00
abstract::Some hybrid foldamers of various length, all containing the (4R,5S)-4-carboxy-5-methyloxazolidin-2-one (d-Oxd) moiety alternating with an l-amino acid (l-Val, l-Lys, or l-Ala), were prepared in order to study their preferred conformations and to evaluate their biological activity. Surprisingly, only the longer oligome...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201600597
更新日期:2017-02-20 00:00:00
abstract::Three photoswitchable tetrapeptides, based on a known synthetic antibacterial, were designed and synthesized to determine activity against Staphylococcus aureus. Each peptide contains an azobenzene photoswitch incorporated into either the N-terminal side chain (1), C-terminal side chain (2), or the C-terminus (3) to a...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.202000280
更新日期:2020-08-19 00:00:00
abstract::The ferrocenyl diphenol complexes 1,1-bis(4'-hydroxyphenyl)-2-ferrocenyl-but-1-ene (1) and 1,2-bis(4'-hydroxyphenyl)-1-ferrocenyl-but-1-ene [(Z)-2], which differ by the relative position of the two phenolic substituents, display dramatically different antiproliferative activities on cancer cells (1 is far more cytotox...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201900430
更新日期:2019-10-04 00:00:00
abstract::Compound 11 (3-(benzyloxy)-1'-methyl-1'-azonia-4H-1'-azaspiro[isoxazole-5,3'-bicyclo[2.2.2]octane] iodide) was selected from a previous set of nicotinic ligands as a suitable model compound for the design of new silent agonists of α7 nicotinic acetylcholine receptors (nAChRs). Silent agonists evoke little or no channe...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201700162
更新日期:2017-08-22 00:00:00
abstract::A series of water-soluble (benzoyloxy)methyl esters of acetylsalicylic acid (ASA), commonly known as aspirin, are described. The new derivatives each have alkyl chains containing a nitric oxide (NO)-releasing nitrooxy group and a solubilizing moiety bonded to the benzoyl ring. The compounds were synthesized and evalua...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201300105
更新日期:2013-07-01 00:00:00