Inhibition of talin-induced integrin activation by a double-hit stapled peptide

Integrins are ubiquitously expressed cell-adhesion proteins. Activation of integrins is triggered by talin through an inside-out signaling pathway, which can be driven by RAP1-interacting adaptor molecule (RIAM) through its interaction with talin at two distinct sites. A helical talin-binding segmen...

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Veröffentlicht in:Structure (London) 2023-08, Vol.31 (8), p.948-957.e3
Hauptverfasser: Gao, Tong, Cho, Eun-ah, Zhang, Pingfeng, Wu, Jinhua
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Sprache:eng
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Zusammenfassung:Integrins are ubiquitously expressed cell-adhesion proteins. Activation of integrins is triggered by talin through an inside-out signaling pathway, which can be driven by RAP1-interacting adaptor molecule (RIAM) through its interaction with talin at two distinct sites. A helical talin-binding segment (TBS) in RIAM interacts with both sites in talin, leading to integrin activation. The bispecificity inspires a “double-hit” strategy for inhibiting talin-induced integrin activation. We designed an experimental peptidomimetic inhibitor, S-TBS, derived from TBS and containing a molecular staple, which leads to stronger binding to talin and inhibition of talin:integrin interaction. The crystallographic study validates that S-TBS binds to the talin rod through the same interface as TBS. Moreover, the helical S-TBS exhibits excellent cell permeability and effectively suppresses integrin activation in cells in a talin-dependent manner. Our results shed light on a new class of integrin inhibitors and a novel approach to design multi-specific peptidomimetic inhibitors. [Display omitted] •We designed a peptidomimetic that inhibits talin-induced integrin activation•S-TBS and TBS bind to talin bispecifically through the same interfaces•S-TBS exhibits stable helical configuration and stronger binding to talin•S-TBS exhibits excellent permeability and suppresses integrin activation Gao et al. provide new insights into the design of integrin inhibitors by targeting integrin:talin interaction through a "double-hit approach" inspired by the bispecificity of RAP1-interacting adaptor molecule (RIAM) toward talin. An RIAM-derived peptidomimetic effectively inhibits integrin activation, shedding light on a promising avenue for the development of intracellular integrin inhibitors.
ISSN:0969-2126
1878-4186
1878-4186
DOI:10.1016/j.str.2023.05.016