Molecularly Imprinted Cavities Template The Macrocyclization Of Tetrapeptides

摘要

Cavities formed using cyclic tetrapeptides (CTPs) or heat-induced conformers act as templates for cyclization; the cavities bind to linear tetrapeptides and enforce turn conformations to enhance cyclization to constrained CTPs.rnConstrained cyclic peptides incorporating (3-turn structures have been designed and studied to provide conformational insight for receptor binding. In a cyclic tetrapeptide ring the distance between C alpha (i) and C alpha (i + 3) is less than 7 A which is suitable for metal ion chelation or incorporating small molecules between the respective side chains. Although CTPs have been isolated and structurally characterized, there has been difficulty in synthesizing derivatives without functional side chains. Typical examples are the antiproliferative agent cyclo-(Pro-Leu-;Pro-Leu) and tyrosinase inhibitor cyclo-(Pro-Val-Pro-Val). Aracil and Francisco reported the synthesis of these two peptides having certain biological activities; other groups tried to resynthesize these compounds, but obtained compounds without the reported biological activities and with different NMR spectra. The cyclo-(Pro-Val-Pro-Val) molecule has a cis-trans-cis-trans backbone-ring conformation. It is possible to build an all-cis cyclic peptide computationally. However, little effort has been made to construct these diverse and novel structures. Macrocycles, not only those with (3-turns, have been prepared using solid-phase methods. Although highly strained CTPs are not readily available, CTP-like molecules ((3-turn mimetics) are important substitutes often used for interaction with protein targets. The low hit rates commonly encountered in high-throughput screening of these analogs suggest that improved macrocyclization approaches to CTP's will be welcomed.