1. Hydrocarbon Stapling-Improved Coupled Folding-Upon-Binding of Peptide-Mediated Interaction between the Nucleocapsid and Phosphoprotein of Human Orthopneumovirus.
- Author
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Shen, Jianqiang, Chen, Meiyuan, Chen, Jianqin, Wu, Jiangang, Shen, Yan, Chen, Yumei, and Wang, Zhaohui
- Subjects
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PEPTIDES , *BIOTIC communities , *HYDROCARBONS , *MEMBRANE fusion , *C-peptide , *NUCLEOPROTEINS - Abstract
Human orthopneumovirus (OPV) is a common respiratory virus that mostly causes respiratory illness in children. Development of therapeutic strategies to treat OPV infection has attracted considerable interest in the medicinal and biological communities. Over the past decades, significant effects have been addressed on disrupting membrane fusion events by targeting viral fusogenic glycoprotein (F-protein) with chemical small-molecule fusion inhibitors. Here, we focus on the rational design of biologic peptide inhibitors to disrupt the peptide-mediated interaction (PMI) between phosphoprotein (P-protein) and nucleoprotein (N-protein) involved in OPV genomic ribonucleoprotein complex. It is revealed that the core 9-mer peptide segment (C-peptide) derived from the C-terminal tail of P-protein is intrinsically disordered in an unbound state but would be structured into an ordered helical conformation when bound to N-protein, representing a biophysical process known as coupled folding-upon-binding. We demonstrated that the process is a compromise between the favorable enthalpy contribution and unfavorable entropy penalty, thus rendering the weak and transient nature of PMI, which could therefore be readily disrupted by competitive agents. Hydrocarbon stapling strategy was used to constrain the helical conformation of C-peptide in an unbound state by chemically introducing an all-hydrocarbon bridge spanning two [ i , i + 4 ] residues of C-peptide. The stapling is observed to considerably enhance the helical propensity of peptide in an unbound state and to effectively improve the binding affinity of peptide to N-protein. Structural modeling analysis suggests that the stapled counterparts can bind to the active site of N-protein in a similar mode with unstapled C-peptide, where the stapled peptide is folded into a helical-like conformation, its anchor residue Phe241 deeply roots in a small druggable pocket of the active site, and the all-hydrocarbon bridge, as designed, is out of N–C complex interface to avoid disrupting the complex interaction. The peptide-mediated interaction between OPV P-protein and N-protein is investigated systematically at structural, energetic and dynamic levels. A C-peptide is derived from the C-terminal tail of P-protein, which exhibits decreased disorder in free state and increased affinity to N-protein upon hydrocarbon stapling. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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