Grafting aminocyclopentane carboxylic acids onto the RGD tripeptide sequence generates low nanomolar alphaVbeta3/alphaVbeta5 integrin dual binders.
Eleven gamma-aminocyclopentane carboxylic acid (Acpca) platforms, including four dihydroxy representatives (19-22), three hydroxy analogues (34-36), and four deoxy derivatives (30-33), were prepared in a chiral nonracemic format. These simple units were then grafted onto an Arg-Gly-Asp (RGD) tripeptide framework by a mixed solid phase/solution protocol delivering an ensemble of 11 macrocyclic analogues of type cyclo-[-Arg-Gly-Asp-Acpca-], 1-11. The individual compounds were evaluated for their binding affinity toward the alphaVbeta3 and alphaVbeta5 integrin receptors. The analogue 10 exhibited a very interesting activity profile (IC50/alphaVbeta3= 1.5 nM; IC50/alphaVbeta5= 0.59 nM), comparable to that of reference compounds EMD121974 and ST1646. Closely related congeners 6, 8, and 9 also proved to be excellent dual binders with activity levels in the low nanomolar range. The three-dimensional (3D) NMR solution structures were determined, and docking studies to X-ray crystal structure of the extracellular segment of integrin alphaVbeta3 in complex with the reference compound EMD121974 were performed on selected analogues to elucidate the interplay between structure and function in these systems and to evidence the subtle bases for receptorial recognition. The results prove that the principle of isosteric dipeptide replacement for peptidomimetics design and synthesis can be violated, without detriment to the development of highly effective integrin binders.
Casiraghi
Giovanni
G
Dipartimento Farmaceutico, Università di Parma, Parco Area delle Scienze 27A, I-43100 Parma, Italy. giovanni.casiraghi@unipr.it
Rassu
Gloria
G
Auzzas
Luciana
L
Burreddu
Paola
P
Gaetani
Enrico
E
Battistini
Lucia
L
Zanardi
Franca
F
Curti
Claudio
C
Nicastro
Giuseppe
G
Belvisi
Laura
L
Motto
Ilaria
I
Castorina
Massimo
M
Giannini
Giuseppe
G
Pisano
Claudio
C
D001667:Binding, Competitive; D018360:Crystallography, X-Ray; D003515:Cycloleucine / Q000737:chemistry*; D039302:Integrin alphaVbeta3 / Q000737:chemistry*; D016023:Integrins / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry; D010456:Peptides, Cyclic / Q000737:chemistry; D011485:Protein Binding; D011869:Radioligand Assay; D019030:Receptors, Vitronectin / Q000737:chemistry*; D012910:Snake Venoms; D012996:Solutions; D013329:Structure-Activity Relationship
D039302:Integrin alphaVbeta3; D016023:Integrins; D009842:Oligopeptides; D010456:Peptides, Cyclic; D019030:Receptors, Vitronectin; D012910:Snake Venoms; D012996:Solutions; C064660:integrin alphaVbeta5; D003515:Cycloleucine; C422910:Cilengitide; C047981:arginyl-glycyl-aspartic acid