High-Affinity α 5 β 1 -Integrin-Selective Bicyclic RGD Peptides Identified via Screening of Designed Random Libraries.

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

We report the identification of high-affinity and selectivity integrin α 5 β 1 -binding bicyclic peptides via "designed random libraries", that is, the screening of libraries comprising the universal integrin-binding sequence Arg-Gly-Asp (RGD) in the first loop in combination with a randomized sequence (XXX) in the second loop. Screening of first-generation libraries for α 5 β 1 -binding peptides yielded a triple-digit nanomolar bicyclic α 5 β 1 -binder ( C T3 RGD c T3 AYG C T3 , IC 50 = 406 nM). Next-generation libraries were designed by partially varying the structure of the strongest first-generation lead inhibitor and screened for improved affinities and selectivities for this receptor. In this way, we identified three high-affinity α 5 β 1 -binders ( C T3 RGD c T3 AYJ C T3 , J = d-Leu, IC 50 = 90 nM; C T3 RGD c T3 AYa C T3 , IC 50 = 156 nM; C T3 RGD c T3 AWG C T3 , IC 50 = 173 nM), of which one even showed a higher α 5 β 1 -affinity than the 32 amino acid benchmark peptide knottin-RGD (IC 50 = 114 nM). Affinity for α 5 β 1 -integrin was confirmed by SPFS analysis showing a K d of 4.1 nM for Cy5-labeled RGD-bicycle C T3 RGD c T3 AYJ C T3 (J = d-Leu) and a somewhat higher K d (9.0 nM) for Cy5-labeled knottin-RGD. The α 5 β 1 -bicycles, for example, C T3 RGD c T3 AYJ C T3 (J = d-Leu), showed excellent selectivities over α v β 5 (IC 50 ratio α 5 β 1 /α v β 5 between <0.009 and

Evidence level

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

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