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131.
Alley SC Benjamin DR Jeffrey SC Okeley NM Meyer DL Sanderson RJ Senter PD 《Bioconjugate chemistry》2008,19(3):759-765
The linker component of antibody-drug conjugates (ADC) is a key feature in developing optimized therapeutic agents that are highly active at well tolerated doses. For maximal intratumoral drug delivery, linkers are required that are highly stable in the systemic circulation, yet allow for efficient drug release at the target site. In this respect, amide bond-based technologies constitute a technological advancement, since the linker half-lives in circulation ( t 1/2 approximately 7 days) are much longer than earlier generation linkers that break down within 1-2 days. The amide linkers, some of which contain peptides, are appended to the mAb carriers through thioether/maleimide adducts. Here, we describe that use of a bromoacetamidecaproyl (bac) in place of the maleimidocaproyl (mc) increases the plasma stability of resulting thioether ADCs. One such ADC, 1F6-C4v2-bac-MMAF, which is directed against the CD70 antigen on lymphomas and renal cell carcinoma, was prepared containing a bac thioether spacer between the drug (MMAF) and the mAb carrier (1F6-C4v2). There was no measurable systemic drug release from this ADC for 2 weeks postadministration in mice. In order to assess the impact of improving linker stability beyond mc containing ADCs, a series of mc and bac-linked 1F6-MMAF conjugates were compared for tolerability, intratumoral drug delivery, and therapeutic efficacy in nude mice with renal cell carcinoma xenografts. There were no statistically significant efficacy differences between sets of mc and bac containing ADCs, although the bac linker technology led to 25% higher intratumoral drug exposure over a 7 day period compared to the corresponding mc linker. The mechanism of drug release from maleimide-adducts likely involves a retro-Michael reaction that takes place in plasma, based on in vitro studies demonstrating that some of the released drug-maleimide derivative became covalently bound to cysteine-34 of serum albumin. In summary, the data indicate that new linkers can be obtained with improved in vivo stability by replacing the maleimide with an acetamide, but the resulting ADCs had similar tolerability and activity profiles. 相似文献
132.
Coffee (Coffea arabica L.) genes early expressed during infection by the rust fungus (Hemileia vastatrix) 总被引:2,自引:0,他引:2
133.
134.
Identification and mapping of protein-protein interactions by a combination of cross-linking, cleavage, and proteomics 总被引:5,自引:0,他引:5
Protein-protein interactions are vital for almost all cellular functions, and many require the formation of multiprotein complexes. Identification of the macroscopic and microscopic protein interactions within these complexes is essential in understanding their mechanisms, both under physiologic as well as pathologic conditions. This review describes the current technology available to investigate interactions between proteins utilizing chemical cross-linking and site-directed cleavage reagents, outlining the necessary steps involved in identifying interacting proteins both in vitro and in vivo. Once interacting proteins are identified, more information about the architecture of the assemblies is necessary. Unique separation techniques coupled with cross-linking and mass spectrometry can now identify specific interaction sites and lead to the development of quaternary structural protein models. Furthermore, combination of these methods with proteomic approaches enables the identification and analysis of complex interactions in vivo. Finally, future directions in cross-linking methodologies are discussed. 相似文献
135.
Proteolysis of the Caulobacter McpA chemoreceptor is cell cycle regulated by a ClpX-dependent pathway
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Proteolysis is involved in cell differentiation and the progression through the cell cycle in Caulobacter crescentus. We have constitutively expressed the transmembrane chemoreceptor McpA from a multicopy plasmid to demonstrate that McpA degradation is modulated during the cell cycle. The level of McpA protein starts to decrease only when the swarmer cells differentiate into stalked cells. The reduction in McpA protein levels is maintained until the stalked cells develop into predivisional cells, at which point the level returns to that observed in swarmer cells. The cell-cycle-regulated degradation of McpA does not require the last 12 C-terminal amino acids, but it does require three amino acids (AAL) located 15 residues away from the C terminus. The ClpXP protease is essential in C. crescentus for viability, and thus, we tested McpA degradation in xylose conditional mutants. The effect on McpA degradation occurred within two generations from the start of ClpX depletion. The conditional mutants' growth rate was only slightly affected, suggesting that ClpX is directly involved in McpA proteolysis. 相似文献
136.
Xianfeng Li Yong-Kang Zhang Jacob J. Plattner Weimin Mao M.R.K. Alley Yi Xia Vincent Hernandez Yasheen Zhou Charles Z. Ding Jinpeng Li Zhijun Shao Hongwei Zhang Musheng Xu 《Bioorganic & medicinal chemistry letters》2013,23(4):963-966
We have designed and synthesized a novel class of compounds based on fluoroquinolone antibacterial prototype. The design concept involved the replacement of the 3-carboxylic acid in ciprofloxacin with an oxaborole-fused ring as an acid-mimicking group. The synthetic method employed in this work provides a good example of incorporating boron atom in complex molecules with multiple functional groups. The antibacterial activity of the newly synthesized compounds has been evaluated. 相似文献
137.
138.
From September 2001 to February 2005, observations of an island population of the New Zealand stitchbird (Notiomystis cincta) revealed a progressive feather-losing dermatitis, which developed during the breeding season around the birds' eyes, base of the bill, and ventral neck. The lesions were significantly more likely to develop in males (96%) than females (51%), with males exhibiting a more severe form of the condition at the end of the breeding season. Histology from a dead bird revealed the presence of ovoid burrowing mites within the lesions, and isolation of mites from skin crusts of a live bird were identified as Knemidocoptes spp. Although other factors might be involved in the expression of the condition, Knemidocoptes appears to be a likely causative agent in the development of skin lesions in this population. 相似文献
139.
Knowledge of structure in biology may help inform hypotheses about function. Little is known about the histological structure or the function of avian facial bristle feathers. Here we provide information on morphology and histology, with inferences for function, of bristles in five predominantly insectivorous birds from New Zealand. We chose species with differing ecologies, including: brown kiwi (Apteryx mantelli), morepork (Ninox novaezealandae), hihi (Notiomystis cincta), New Zealand robin (Petroica australis), and New Zealand fantail (Rhipidura fuliginosa). Average bristle length corrected for body size was similar across species. Bristles occurred in distinct groups on different parts of the head and upper rictal bristles were generally longest. The lower rictal bristles of the fantail were the longest possessed by that species and were long compared to bristles of other species. Kiwi were the only species with forehead bristles, similar in length to the upper rictal bristles of other species, and the lower rictal bristles of fantails. Herbst corpuscles (vibration and pressure sensitive mechanoreceptors) were found in association with bristle follicles in all species. Nocturnal and hole‐nesting birds had more heavily encapsulated corpuscles than diurnal open‐nesting species. Our results suggest that avian facial bristles generally have a tactile function in both nocturnal and diurnal species, perhaps playing a role in prey handling, gathering information during flight, navigating in nest cavities and on the ground at night and possibly in prey‐detection. These differing roles may help explain the observed differences in capsule thickness of the corpuscles. J. Morphol., 2011. © 2010 Wiley‐Liss, Inc. 相似文献
140.
K E Alley 《Journal of neurobiology》1990,21(7):1092-1107
Maturation of vertebrate neuromuscular systems typically occurs in a continuous, orderly progression. After an initial period of developmental adjustment by means of cell death and axonal pruning, relatively stable relationships, with only subtle modifications, are maintained between motoneurons and their appropriate targets throughout life. However, among a restricted group of vertebrates (amphibians and especially the anuran amphibians) the sequential maturation of neuromuscular systems is altered by an abrupt reordering of the basic body plan that encompasses cellular changes in all tissues from skeleton to nervous system. Many anuran amphibians possess neuromuscular circuits that are remarkable by virtue of their complete reorganization during the brief span of metamorphosis. During this period motor systems initially designed for the behavioral patterns of aquatic tadpoles are adjusted to meet the drastically different motor activities of postmetamorphic terrestrial life. This adjustment involves the deletion of neural elements mediating larval specific activities, the accelerated maturation of neural circuits eliciting adult-specific activities and the retrofitting of larval neuromuscular components to serve postmetamorphic behaviors. This review focuses on the cellular events associated with the neuromuscular adaptation in the jaw complex during metamorphosis of the leopard frog, Rana pipiens. As part of the metamorphic reorganization of the jaw apparatus there is a complete turnover of the myofiber complement of the adductor mandibulae musculature. Trigeminal motoneurons initially deployed to the larval myofibers are redirected to new muscle fibers. Simultaneously the cellular geometry and synaptic input to these motoneurons is revamped. These changes suggest that trigeminal neuromuscular circuitry established during embryogenesis is updated during metamorphosis and reused to provide the basis for adult jaw motor activity that is far different than its larval counterpart. 相似文献