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41.
TBPB and 77-LH-28-1 are selective agonists of the M1 muscarinic acetylcholine receptor (mAChR) that may gain their selectivity through a bitopic mechanism, interacting concomitantly with the orthosteric site and part of an allosteric site. The current study combined site-directed mutagenesis, analytical pharmacology,and molecular modeling to gain further insights into the structural basis underlying binding and signaling by these agonists. Mutations within the orthosteric binding site caused similar reductions in affinity and signaling efficacy for both selective and prototypical orthosteric ligands. In contrast, the mutation of residues within transmembrane helix (TM) 2 and the second extracellular loop (ECL2) discriminated between the different classes of ligand. In particular, ECL2 appears to be involved in the selective binding of bitopic ligands and in coordinating biased agonism between intracellular calcium mobilization and ERK1/2 phosphorylation. Molecular modeling of the interaction between TBPB and the M1 mAChR revealed a binding pose predicted to extend from the orthosteric site up toward a putative allosteric site bordered by TM2, TM3, and TM7, thus consistent with a bitopic mode of binding. Overall, these findings provide valuable structural and mechanistic insights into bitopic ligand actions and receptor activation and support a role for ECL2 in dictating the active states that can be adopted by a G protein-coupled receptor. This may enable greater selective ligand design and development for mAChRs and facilitate improved identification of bitopic ligands.  相似文献   
42.
Voltage-gated sodium (NaV) channels initiate and propagate action potentials in excitable tissues to mediate key physiological processes including heart contraction and nervous system function. Accordingly, NaV channels are major targets for drugs, toxins and disease-causing mutations. Recent breakthroughs in cryo-electron microscopy have led to the visualization of human NaV1.1, NaV1.2, NaV1.4, NaV1.5 and NaV1.7 channel subtypes at high-resolution. These landmark studies have greatly advanced our structural understanding of channel architecture, ion selectivity, voltage-sensing, electromechanical coupling, fast inactivation, and the molecular basis underlying NaV channelopathies. NaV channel structures have also been increasingly determined in complex with toxin and small molecule modulators that target either the pore module or voltage sensor domains. These structural studies have provided new insights into the mechanisms of pharmacological action and opportunities for subtype-selective NaV channel drug design. This review will highlight the structural pharmacology of human NaV channels as well as the potential use of engineered and chimeric channels in future drug discovery efforts.  相似文献   
43.
目的 分析抚顺地区泌尿生殖道解脲支原体和人型支原体感染情况及药敏情况。方法 采用支原体培养、鉴定、药敏一体化试剂盒对710名患者进行解脲支原体(Uu)和人型支原体(Mh)检测和其对9种抗菌药物的药敏试验。结果 710名患者中共检出支原体感染者200名,阳性率为28.17%。其中Uu 140名(19.71%),Mh 12名(1.69%),Uu+Mh混合感染48名(6.76%)。药敏结果表明,支原体对强力霉素、美满霉素和克拉霉素敏感率高,分别为95.71%,98.57%和91.42%。结论 抚顺地区支原体感染发病率较高,以单纯Uu感染为主,美满霉素是治疗支原体感染的首选药物。  相似文献   
44.
GABA_B受体变构剂药学研究进展   总被引:1,自引:0,他引:1  
γ-氨基丁酸B受体(GABAB receptor,GABABR)是最具有药理学意义的药物靶点之一,具有复杂而精细的激活机制。传统的GABABR靶点药物开发集中于激动剂和拮抗剂,这类药物受到多种因素的制约,包括较强的副作用、药物代谢困难、机体耐药性明显等。变构剂结合于正构位点之外,能够调节GABABR异源二聚体亚基或结构域间的相互作用。正向变构剂(positiveallosteric modulators,PAMs)和负向变构剂(negative allosteric modulators,NAMs)分别可以提高或降低GABABR的活性,并具有较高的特异性和药物安全性,同时还能够保持GABABR信号在时间和空间上的可控性。变构剂为GABABR靶点药物开发提供了新思路。  相似文献   
45.
Designed peptides that would selectively interact with lipopolysaccharide (LPS) or endotoxin and fold into specific conformations could serve as important scaffolds toward the development of antisepsis compounds. Here, we describe solution structure of a designed amphipathic peptide, H2N-YVKLWRMIKFIR-CONH2 (YW12D) in complex with endotoxin as determined by transferred nuclear Overhauser effect spectroscopy. The conformation of the isolated peptide is highly flexible, but undergoes a dramatic structural stabilization in the presence of LPS. Structure calculations reveal that the peptide presents two amphipathic surfaces in its bound state to LPS whereby each surface is characterized by two positive charges and a number of aromatic and/or aliphatic residues. ITC data suggests that peptide interacts with two molecules of lipid A. In activity assays, YW12D exhibits neutralization of LPS toxicity with very little hemolysis of red blood cells. Structural and functional properties of YW12D would be applicable in designing low molecular weight non-toxic antisepsis molecules.  相似文献   
46.
目的探讨育龄妇女泌尿生殖道无乳链球菌感染情况与耐药性。方法选择3 000例在我院就诊的育龄期妇女,所有患者送检泌尿道或生殖道标本,进行无乳链球菌培养及药物敏感性试验,探讨育龄妇女泌尿生殖道无乳链球菌感染情况及耐药性。结果 3 000例育龄妇女中177例感染无乳链球菌,感染率5.90%,其中肾内科患者感染率最高,达到8.97%。2012至2015年育龄期妇女无乳链球菌感染率逐年增加。无乳链球菌对四环素、克林霉素、红霉素、左氧氟沙星耐药性较高,分别达到80.80%、60.45%、56.50%、45.20%。无乳链球菌对头孢曲松、头孢他啶、亚胺培南、万古霉素未产生耐药性。结论育龄妇女无乳链球菌感染率较高,呈逐年上升趋势,防治形势严峻,无乳链球菌对多种常用抗生素耐药率较高,应根据药敏结果合理使用抗生素。  相似文献   
47.
48.
The Trypanosoma spp. cause animal and human trypanosomiasis characterized with appreciable health and economic burden mostly in developing nations. There is currently no effective therapy for this parasitic disease, due to poor drug efficacy, drug resistance, and unwanted toxicity, etc. Therefore, new anti-Trypanosoma agents are urgently needed. This study explored new series of imidazoles for anti-Trypanosoma properties in vitro and in vivo. The imidazoles showed moderate to strong and specific action against growth of T. congolense. For example, the efficacy of the imidazole compounds to restrict Trypanosoma growth in vitro was ≥ 12-fold specific towards T. congolense relative to the mammalian cells. Additionally, the in vivo study revealed that the imidazoles exhibited promising anti-Trypanosoma efficacy corroborating the in vitro anti-parasite capacity. In particular, three imidazole compounds (C1, C6, and C8) not only cleared the systemic parasite burden but cured infected rats after no death was recorded. On the other hand, the remaining five imidazole compounds (C2, C3, C4, C5, and C7) drastically reduced the systemic parasite load while extending survival time of the infected rats by 14 days as compared with control. Untreated control died 3 days post-infection, while the rats treated with diminazene aceturate were cured comparable to the results obtained for C1, C6, and C8. In conclusion, this is the first study demonstrating the potential of these new series of imidazoles to clear the systemic parasite burden in infected rats. Furthermore, a high selectivity index of imidazoles towards T. congolense in vitro and the oral LD50 in rats support anti-parasite specific action. Together, findings support the anti-parasitic prospects of the new series of imidazole derivatives.  相似文献   
49.
Only a few novel classes of antiparasitic drugs have emerged over the last few decades, reflecting the difficulties associated with bringing a safe, effective molecule to market. In recent years, the screening paradigm has shifted from empirical whole parasite screening towards mechanism-based high throughput screening. This approach requires investment in molecular parasitology and in understanding the basic biology of parasites, as well as requiring considerable investment in an infrastructure for screening. Add to this the fact that the drug discovery process is iterative with high attrition, the Animal Health industry by necessity must focus on discovering medicines for diseases, which will deliver a return on investment. In recent years the rapid progression of genomics has unlocked a plethora of tools for target identification, validation and screening, revolutionising mechanism-based screening for antiparasitic drug discovery. The challenge still remains; however, to identify novel chemical entities with the properties required to deliver a safe, effective antiparasitic drug.  相似文献   
50.
We synthesized a pair of compounds containing leucine zipper peptides to deliver protein cargo into cells. One is a cell-penetrating peptide (CPP) with Lz(E), a leucine zipper peptide containing negatively charged amino acids, and the other is a Nanog protein with Lz(K), a leucine zipper peptide containing positively charged amino acids. When cells were treated with these equimolar mixtures, Nanog-Lz(K) hybridized with Lz(E)-CPP was successfully delivered into the cells. Furthermore, Nanog-Lz(K) exerted its proper function after nuclear transport.  相似文献   
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