Computational Design of Macrocyclic Binders of S100B(ββ): Novel Peptide Theranostics

• Published in: Molecules (Basel, Switzerland) Vol. 26; no. 3; p. 721
• Main Authors: Kannan, Srinivasaraghavan, Aronica, Pietro G. A., Nguyen, Thanh Binh, Li, Jianguo, Verma, Chandra S.
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 30.01.2021; MDPI
• Subjects: Amino acids; Computer Simulation; Crystal structure; Humans; Inflammation - genetics; Inflammation - therapy; Kinases; Melanoma; Models, Molecular; molecular dynamics; Molecular Dynamics Simulation; Multiple myeloma; Neoplasms - genetics; Neoplasms - therapy; peptide design; Peptide Fragments - chemistry; Peptide Fragments - genetics; Peptides; Permeability; PPI; Precision Medicine; Protein Binding - genetics; Protein Interaction Maps - genetics; Proteins; S100 Calcium Binding Protein beta Subunit - chemistry; S100 Calcium Binding Protein beta Subunit - genetics; S100 Calcium Binding Protein beta Subunit - ultrastructure; S100B; Skin cancer; stapled peptides; Traumatic brain injury; PPI; peptide design; stapled peptides; S100B; molecular dynamics
• ISSN: 1420-3049; 1420-3049
• 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.