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Cyclic peptide substrates of pp60c-src. Synthesis and evaluation
J S McMurray1, R J Budde, D F Dyckes
1Department of Neuro-Oncology, University of Texas M.D. Anderson Cancer Center, Houston.
International Journal of Peptide and Protein Research
|September 1, 1993
Summary
Cyclic peptides were synthesized and tested against pp60c-src kinase. Inserting D-Phe-Pro altered kinetic parameters, showing higher Vmax but similar Km compared to linear substrates.
Area of Science:
- Biochemistry
- Molecular Biology
- Medicinal Chemistry
Background:
- pp60c-src is a proto-oncogene product implicated in cancer.
- Understanding peptide substrate kinetics is crucial for drug development.
- Cyclic peptides offer conformational constraints that can influence biological activity.
Purpose of the Study:
- To investigate how constrained conformation and amino acid sequence affect peptide kinetic parameters.
- To synthesize and evaluate cyclic peptides as substrates and inhibitors of pp60c-src.
- To compare the kinetic properties of cyclic peptides with their linear counterparts.
Main Methods:
- Solid-phase peptide synthesis (SPPS) using Fmoc chemistry.
- Cleavage from resin and cyclization using BOP reagent.
- Kinetic analysis of peptide substrates and inhibitors for pp60c-src activity.
- Comparison with linear analogues and Val-5 angiotensin II.
Main Results:
- Cyclization had minimal impact on the binding (Ki, Km) and phosphorylation rate (Vmax) of simple cyclic peptides.
- Incorporation of a D-Phe-Pro dipeptide into cyclic decapeptides significantly altered kinetic parameters (Ki, Km, Vmax).
- D-Phe-Pro containing cyclic peptides exhibited higher Vmax values than linear substrates, with comparable Km values in the millimolar range.
Conclusions:
- Constrained conformation via cyclization has a limited effect on pp60c-src kinetics for certain sequences.
- Specific amino acid insertions, like D-Phe-Pro, can dramatically modulate peptide substrate efficiency.
- These findings provide insights into the design of peptide-based modulators of pp60c-src activity.
