<i>N</i>-Methylated Cyclic RGD Peptides as Highly Active and Selective α_Vβ₃Integrin Antagonists

TLDR

The αVβ3 integrin is key in tumor metastasis and angiogenesis, and its inhibition by antibodies or cyclic RGD peptides is a promising therapeutic strategy. The study examines how N‑methylation of the cyclo(RGDfV) antagonist L1 affects its biological activity. The authors used N‑methylated cyclo(RGDfV) analogs and characterized their structure by NMR, distance geometry, and molecular dynamics to elucidate structure‑activity relationships. P5, an N‑methylated analog, exhibited higher activity and selectivity than L1 in blocking vitronectin binding to αVβ3, with its structure elucidated by NMR and computational methods.

Abstract

The alpha(V)beta(3) integrin receptor plays an important role in human tumor metastasis and tumor-induced angiogenesis. The in vivo inhibition of this receptor by antibodies or by cyclic peptides containing the RGD sequence may in the future be used to selectively suppress these diseases. Here we investigate the influence of N-methylation of the active and selective alpha(V)beta(3) antagonist cyclo(RGDfV) (L1) on biological activity. Cyclo(RGDf-N(Me)V-) (P5) was found to be even more active than L1 and is one of the most active and selective compounds in inhibiting vitronectin binding to the alpha(V)beta(3) integrin. Its high-resolution, three-dimensional structure in water was determined by NMR techniques, distance geometry calculations, and molecular dynamics calculations, providing more insight into the structure-activity relationship.