Granulocyte-macrophage colony-stimulating factor mimicry and receptor interactions.
Granulocyte-macrophage colony-stimulating factor mimicry and receptor interactions.
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粒细胞-巨噬细胞集落刺激因子模拟和受体相互作用。
DOI：
10.1007/bf02918271
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发表时间：
1994
影响因子：
4.4
通讯作者：
Williams,WV
中科院分区：
文献类型：
--
作者：
VonFeldt,JM;Monfardini,C;Kieber-Emmons,T;Voet,D;Weiner,DB;Williams,WV
开发大分子多肽配体的小分子模拟物是设计药效团的重要途径。开发这类模拟物的一种策略是分析与天然配体结合在同一位置的替代配体。这些允许在不同的主干几何设置内检查结合的结构和化学约束。抗受体抗体作为替代配体的使用使生物活性多肽在几种配体-受体系统中得以发展。该技术已应用于人粒细胞-巨噬细胞集落刺激因子(GM-CSF)及其受体(GM-CSFR)相互作用的研究。GM-CSF是一类信号转导细胞因子和生长因子家族，其核心结构为四股螺旋结构。GM-CSFR是由GM-CSFR的α链(GM-CSFRα)和与IL-3和IL-5受体共有的β链(βc)组成。GM-CSF上至少有两个位点与GM-CSF-GM-CSFRα/β三元复合体有关。在这里总结的研究中，设计了GM-CSF序列的合成肽类似物并用于绘制中和表位图。一个中和表位对应于GM-csf的A螺旋，一个合成的类似物在体外显示了作为GM-csf拮抗剂的生物学活性，表明它与GM-CSFRα/β复合体相互作用。由B和C螺旋组成的第二个多肽被单抗中和识别，并显示类似的拮抗活性。同时采用重组抗体(RAb)技术。建立了抗GM-CSF中和性抗体免疫的小鼠RAB表达文库，并用中和抗体进行筛选。一个显示受体结合活性的克隆与GM-CSF上的表位在结构上相似，先前被认为是与中和单抗的相互作用部位。Rab的合成肽类似物可抑制GM-CSF的生物活性。根据Rab多肽和GM-CSF的结构相似性预测临界接触残基。这些研究表明了在生物活性多肽设计中使用RABS的可行性，为药物设计提供了先导化合物和有关接触残留物的信息。
Development of small molecular mimics of larger polypeptide ligands is an important approach to pharmacophore design. One strategy for the development of such mimics is analysis of alternative ligands that bind to the same site as the native ligand. These allow examination of the structural and chemical constraints for binding within the setting of diverse backbone geometries. The use of antireceptor antibodies as alternative ligands has allowed the development of biologically active peptides in several ligand-receptor systems. This technology has been applied to the study of interactions between human granulocyte-macrophage colony-stimulating factor (GM-CSF) and its receptor (GM-CSFR). GM-CSF is one of a family of signal-transducing cytokines and growth factors characterized by a fourhelix bundle core structure. The GM-CSFR is comprised of an α-chain (GM-CSFRα) specific for GM-CSF, and a β-chain (βc) shared with the interleukin-3 and interleukin-5 receptors. At least two sites on GM-CSF have been implicated in the GM-CSF-GM-CSFRα/βcternary complex. In studies summarized here, synthetic peptide analogs of GM-CSF sequences were designed and used to map neutralizing epitopes. One neutralizing epitope corresponded to the A helix of GM-CSF, and a synthetic analog displayed biological activity as a GM-CSF antagonist in vitro, suggesting interaction with the GM-CSFRα/βccomplex. A second peptide comprising the B and C helices was recognized by monoclonal neutralizing antibodies and similarly displayed antagonist activity. Recombinant antibody (rAb) technology was also employed. An expression library of rAbs from mice immunized with neutralizing anti-GM-CSF antibodies was developed and screened with a neutralizing anti-GM-CSF monoclonal antibody. One clone which displayed receptor binding activity exhibited structural similarity with epitopes on GM-CSF previously implicated as interaction sites with the neutralizing monoclonal antibody. A synthetic peptide analog of the rAb inhibited GM-CSF bioactivity. Critical contact residues were predicted on the basis of structural similarity of the rAb peptide and GM-CSF. These studies in dicate the feasibility of using rAbs in bioactive peptide design, providing lead compounds and information regarding contact residues for drug design.