The peptidomimetic Vasotide targets two retinal VEGF receptors and reduces pathological angiogenesis in murine and nonhuman primate models of retinal disease

Abstract

Blood vessel growth from preexisting vessels (angiogenesis) underlies many severe diseases including major blinding retinal diseases such as retinopathy of prematurity (ROP) and aged macular degeneration (AMD). This observation has driven development of antibody inhibitors that block a central factor in AMD, named vascular endothelial growth factor (VEGF), from binding to its receptors VEGFR-1 and VEGFR-2. However, some patients are insensitive to current anti-VEGF drugs or develop resistance, and the required repeated intravitreal injection of these large molecules is costly and clinically problematic. Here, we have evaluated a small cyclic retro-inverted peptidomimetic, D(Cys-Leu-Pro-Arg-Cys), abbreviated as D(CLPRC), and hereafter named Vasotide, that inhibits retinal angiogenesis by binding selectively to the VEGF receptors, VEGFR-1 and Neuropilin-1 (NRP-1). Delivery of Vasotide in eye drops or via intraperitoneal injection in a laser-induced monkey model of human wet AMD, a mouse genetic knockout model of the AMD subtype called retinal angiomatous proliferation (RAP), and a mouse oxygen-induced model of retinopathy of prematurity (ROP) markedly decreased retinal angiogenesis in all three animal models. This prototype drug candidate is a promising new dual receptor inhibitor of the VEGF ligand with potential for translation into safer, less invasive applications to combat pathological angiogenesis in retinal disorders.

Discovery of pan-VEGF inhibitory peptides directed to the extracellular ligand-binding domains of the VEGF receptors

“…As expected, normal C57BL/6 mice that were not subjected to the OIR model have a homogeneous vascular layer of approximately 39 ± 1.3 μm (Fig. 8D) that is positioned between the ganglion and the outer plexiform layers of the normal retina ( 19 ). When mice are treated by OIR, the vascular layer changes shape and becomes thicker (75 ± 2.7 μm) because of a series of tufts of vessels extending toward the vitreous humor (Fig.…”

“…In a previous study ( 19 ), we have successfully developed a small tripeptide (now denominated Vasotide) into a prodrug candidate. Nevertheless, it is not very often that peptides are suitable for drug development.…”

Ocular delivery of proteins and peptides: Challenges and novel formulation approaches

“…Such potential of Vasotide peptide in binding two important VEGFRs and at the same time blocking additional mechanisms holds promise for further translation into safer, less-invasive applications in retinal disorders (Fig. 4)[25]. Current anti-VEGF therapies are approved for neovascular (wet) AMD and diabetic macular edema (DME).…”

Importância do domínio extracelular do receptor tirosina quinase Tie1 na angiogênese

“…Anticorpos são estáveis, possuem um peso molecular que previne a sua eliminação através da depuração renal e a sua porção Fc interage com vários receptores em diferentes tipos celulares, o que aumenta a sua biodisponibilidade na circulação sanguínea (CHAMES et al, 2009 (GIORDANO et al, 2010;BONO et al, 2013;SIDMAN et al, 2015).…”

“…Em trabalhos anteriores mostramos que um pequeno peptídeo específico do domínio extracelular de ligação do ligante de VEGFR1 e de NRP1 (GIORDANO et al, 2001;GIORDANO et al, 2005) inibiu a neovascularização da retina (GIORDANO et al, 2010). Este peptídeo, que pode ser aplicado topicamente ao olho, combina a seletividade de um anticorpo monoclonal com as vantagens de uma pequena molécula, enfatizando o potencial para o direcionamento do domínio extracelular de receptores transmembrana envolvidos na angiogênese (GIORDANO et al, 2010;SIDMAN et al, 2015).…”