Structure–Activity Relationship of RGD-Containing Cyclic Octapeptide and αvβ3 Integrin Allows for Rapid Identification of a New Peptide Antagonist

International Journal of Molecular Sciences

Wei Wang¹  Heng Wei Chang¹  Yan Wang¹  Kit S. Lam²  Wenwu Xiao²  Yonghong Zhang³  Aaron Silva³  James B. Ames⁴ 

[1] CSBio Company Inc, Menlo Park, CA 94025, USA;Department of Biochemistry and Molecular Medicine, University of California, Davis Cancer Center, Sacramento, CA 95616, USA;Department of Chemistry, The University of Texas Rio Grande Valley, Edinburg, TX 78539, USA;Department of Chemistry, University of California, Davis, CA 95616, USA;

关键词: integrin αvβ3 antagonists;    RGD peptides;    structure–activity relationship;    in silico screening;    in vitro binding;   

DOI  :  10.3390/ijms21093076

来源: DOAJ

【 摘 要 】

The αvβ3 integrin, a receptor for many extracellular matrix proteins with RGD-sequence motif, is involved in multiple physiological processes and highly expressed in tumor cells, therefore making it a target for cancer therapy and tumor imaging. Several RGD-containing cyclic octapeptide (named LXW analogs) were screened as αvβ3 antagonists with dramatically different binding affinity, and their structure–activity relationship (SAR) remains elusive. We performed systematic SAR studies and optimized LXW analogs to improve antagonistic potency. The NMR structure of LXW64 was determined and docked to the integrin. Structural comparison and docking studies suggested that the hydrophobicity and aromaticity of the X7 amino acid are highly important for LXW analogs binding to the integrin, a potential hydrophobic pocket on the integrin surface was proposed to play a role in stabilizing the peptide binding. To develop a cost-efficient and fast screening method, computational docking was performed on LXW analogs and compared with in vitro screening. A consistency within the results of both methods was found, leading to the continuous optimization and testing of LXW mutants via in silico screening. Several new LXW analogs were predicted as the integrin antagonists, one of which—LXZ2—was validated by in vitro examination. Our study provides new insight into the RGD recognition specificity and valuable clues for rational design of novel αvβ3 antagonists.

【 授权许可】

Unknown