Role of Side‐Chain Bioisosteres in Determining the Binding Affinity of Click Chemistry Derived RGD Peptidomimetics to αvβ3 Integrin1. Issue 34 (24th October 2014) - Fabbrizzi, Pierangelo
Abstract: Triazole‐containing Arg‐Gly‐Asp (RGD) peptidomimetics capable of interacting with αv β3 integrin were developed through click chemistry. The role of the diverse range of guanidine bioisosteres for the arginine mimetic moiety was evaluated in vitro together with different appendages on the aspartic acid side of the peptidomimetic. The corresponding azides and alkynes were constructed through the application of simple modular reactions. Integrin binding assays allowed the best guanidine bioisostere for binding activity to be selected; the aromatic ring at the azide fragment bearing the aspartic acid moiety proved to be unnecessary. Molecular modelling calculations of a hit compound showed that the triazole and 2‐aminopyridine rings were involved in important π‐stacking interactions with Tyr178. Abstract : Click chemistry was used to build a series of nonpeptide Arg‐Gly‐Asp (RGD) peptidomimetics. Integrin binding assays revealed heterocyclic guanidine bioisosteres that showed binding activity and also indicated a minor role played by the aromatics on the azide fragment. Modelling showed that the triazole and 2‐aminopyridine rings interact with Tyr178 of αv β3 integrin.