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- Title
Structure-Based Optimization of Therapeutic Peptide Selectivity Between Cerebrovascular Rho-1 and Rho-2 Kinase Isoforms.
- Authors
Gu, Zhengtian; Yan, Tingting; Yan, Fuling
- Abstract
The cerebrovascular Rho kinase pathway has been implicated in the pathogenesis of central nervous system disorders, which is regulated by two highly homologous isoforms Rho-1 and Rho-2. Selective targeting of the two kinase isoforms can result in potent but distinct therapeutic effects on diverse cerebrovascular diseases. However, the two kinases share a very high conservation in kinase domain and are fully identical in ATP-binding site, making traditional small-molecule inhibitors unable to effectively distinguish between them. Instead, we propose use of therapeutic peptide agents to selectively disrupt their dimerization domain, where has only a relatively low homology. The dimerization domain is composed of three helices H1–H3, from which the H1 helix is split to derive a self-inhibitory peptide that may rebind at kinase dimerization interface to competitively disrupt the dimerization. The peptide is used as start to generate a number of isoform-selective peptides with a structure-based optimization strategy. Consequently, four and three H1-derived peptides are rationally designed to have strong selectivity for Rho-1 over Rho-2 and for Rho-2 over Rho-1, respectively, altough their affinity to the two kinases is generally moderate since the optimization strategy accepts peptide affinity degradation in order to maximize the peptide selectivity. The selectivity is improved from ~ 1.5-fold for native H1 peptide to > threefold for optimized peptides. Structural analysis reveals that the peptide residues can be classified into specific, stable and marginal, which confer selectivity, affinity and nothing to the kinase–peptide binding, respectively.
- Subjects
CENTRAL nervous system; CEREBROVASCULAR disease; TREATMENT effectiveness; DIMERIZATION
- Publication
International Journal of Peptide Research & Therapeutics, 2020, Vol 26, Issue 4, p2419
- ISSN
1573-3149
- Publication type
Article
- DOI
10.1007/s10989-020-10032-8