Shifting Towards α_Vβ₆ Integrin Ligands Using Novel Aminoproline‐Based Cyclic Peptidomimetics

Abstract

In recognition of the key role played by integrins in several life-threatening dysfunctions,t he search for novel small-molecule probes that selectively recognize these surface receptors is still open and widely pursued. Inspired by previously established aminoproline (Amp)-RGD based cyclopeptidomimeticswith attracting a V b 3 integrin affinity and selectivity,t he designa nd straightforward synthesis of 18 new AmpRGD chemotypes bearinga dditional structuralv ariants were herein implemented, to shift toward peptide-like a V b 6 integrin targeted binders. The ligand competence of the synthesized products toward a V b 6 was evaluatedi nc ompetitive bindinga ssays on isolated receptors, and a V b 6 /a V b 3 selectivity was determined for as ubgroup of compounds, resulting in the identification of four very promising candidates. SAR considerations and docking simulations allowed us to appreciate the key structural features responsible for the observed activity.

Halting the Spread of Herpes Simplex Virus-1: The Discovery of an Effective Dual αvβ6/αvβ8 Integrin Ligand

“…Nonetheless, while many ligands are available for αIIbβ3, αvβ3, and α5β1, 28 − 37 few selective binders are known for αvβ6 and αvβ8. 38 − 43 In this regard, we recently identified a cyclic pentapeptide, namely, [RGD-Chg-E]-CONH 2 ( 1 ) ( Chart 1 ), as a potent and preferential αvβ6 ligand, 39 which was successfully converted into an effective probe for molecular imaging. 42 Considering that herpesviruses employ both αvβ6 and αvβ8 as co-receptors for cellular entry, a dual ligand of these integrins should represent a more efficient anti-HSV agent than the corresponding mono-αvβ6- or αvβ8-selective binders.…”

New 4-Aminoproline-Based Small Molecule Cyclopeptidomimetics as Potential Modulators of α4β1 Integrin

“…High resolution mass analysis (ESI) was performed on LTQ ORBITRAP XL Thermo apparatus and are reported in the form of ( m / z ). (2 S ,4 S )-4- N -(9-Fluorenylmethoxycarbonyl)aminoproline ( 20 ) and 4-[[[(2-methylphenyl)amino] carbonyl]amino]phenylacetic acid (MPUPA-OH) ( 21 ) were prepared according to the literature procedures [ 22 , 32 ].…”

“… Amp-based cyclopeptides directed to RGD-recognizing α V β 3 , α V β 5 , and α V β 6 integrins (compounds 5 and 6 ) [ 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ], and general structure of cyclopeptidomimetics 7 designed and synthesized to target α 4 β 1 integrin in the present study. …”

“…In recent years, the exploitation of the cis -4-amino-L-proline residue (Amp) as a conformation-inducing scaffold led to the development of novel classes of RGD-based cyclopeptide ligands of type 5 and 6 ( Figure 2 ) targeting α V β 3 , α V β 5 , and/or α V β 6 integrin receptors with a good-to-high-affinity and selectivity [ 30 , 31 , 32 ]. These integrins are known to be directly involved in the evolution and diffusion of metastatic tumor cells and angiogenesis, as well as in the development of organ fibrosis.…”

αVβ6 Integrin: An Intriguing Target for COVID‐19 and Related Diseases

“…Interestingly, George and colleagues suggested that novel antifibrotic drugs targeting α V β 6 may prevent the development of severe SARS‐CoV‐2 infection. [17] Potent and selective α V β 6 integrin ligands have been recently published in literature, [18] such as the nonapeptide α V β 6 antagonist c [FRGDLAFp(NMe)K] (I, Figure 1 ), [19] the cyclopeptide c (RGD‐Chg‐E)‐CONH 2 (II, Figure 1 ), [20] the peptidomimetic c (Amp)LRGDL (III, Figure 1 ) [21] and the non‐peptidic small‐molecule inhibitor developed by GSK (IV, GSK3008348, Figure 1 , discussed in the following paragraph). [22] …”