Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR), 30 Biopolis Street, #07-01 Matrix, Singapore 138671, Singapore.
Singapore Eye Research Institute, Singapore 169856, Singapore.
Molecules. 2021 Jan 30;26(3):721. doi: 10.3390/molecules26030721.
S100B(ββ) proteins are a family of multifunctional proteins that are present in several tissues and regulate a wide variety of cellular processes. Their altered expression levels have been associated with several human diseases, such as cancer, inflammatory disorders and neurodegenerative conditions, and hence are of interest as a therapeutic target and a biomarker. Small molecule inhibitors of S100B(ββ) have achieved limited success. Guided by the wealth of available experimental structures of S100B(ββ) in complex with diverse peptides from various protein interacting partners, we combine comparative structural analysis and molecular dynamics simulations to design a series of peptides and their analogues (stapled) as S100B(ββ) binders. The stapled peptides were subject to in silico mutagenesis experiments, resulting in optimized analogues that are predicted to bind to S100B(ββ) with high affinity, and were also modified with imaging agents to serve as diagnostic tools. These stapled peptides can serve as theranostics, which can be used to not only diagnose the levels of S100B(ββ) but also to disrupt the interactions of S100B(ββ) with partner proteins which drive disease progression, thus serving as novel therapeutics.
S100B(ββ) 蛋白是一组多功能蛋白，存在于多种组织中，调节广泛的细胞过程。它们的表达水平改变与多种人类疾病有关，如癌症、炎症性疾病和神经退行性疾病，因此作为治疗靶点和生物标志物受到关注。S100B(ββ) 的小分子抑制剂已取得有限的成功。在大量现有的 S100B(ββ) 与来自各种蛋白质相互作用伙伴的不同肽的复杂结构的指导下，我们结合比较结构分析和分子动力学模拟来设计一系列肽及其类似物（订书肽）作为 S100B(ββ) 结合物。订书肽经过计算机诱变实验，得到了预测与 S100B(ββ) 高亲和力结合的优化类似物，并进一步修饰成像剂作为诊断工具。这些订书肽可以作为治疗诊断剂，不仅可以用于诊断 S100B(ββ) 的水平，还可以用于破坏 S100B(ββ) 与驱动疾病进展的伴侣蛋白的相互作用，从而成为新的治疗方法。
