Neuropilin (NRPs) Related Pathological Conditions and Their Modulators

Abstract

Neuropilin 1 (NRP1) represents one of the two homologous neuropilins (NRP, splice variants of neuropilin 2 are the other) found in all vertebrates. It forms a transmembrane glycoprotein distributed in many human body tissues as a (co)receptor for a variety of different ligands. In addition to its physiological role, it is also associated with various pathological conditions. Recently, NRP1 has been discovered as a coreceptor for the SARS-CoV-2 viral entry, along with ACE2, and has thus become one of the COVID-19 research foci. However, in addition to COVID-19, the current review also summarises its other pathological roles and its involvement in clinical diseases like cancer and neuropathic pain. We also discuss the diversity of native NRP ligands and perform a joint analysis. Last but not least, we review the therapeutic roles of NRP1 and introduce a series of NRP1 modulators, which are typical peptidomimetics or other small molecule antagonists, to provide the medicinal chemistry community with a state-of-the-art overview of neuropilin modulator design and NRP1 druggability assessment.

Keywords: COVID-19; cancer; computer-aided drug design; in silico drug design; neuropathic pain; neuropilins; peptidomimetics; receptor modulator design; small-molecule antagonists.

Figure 2

(a) A 2D representation of the VEGF-A165 CendR (KPRR) motif. Hydrogen bonding and salt bridge interactions, crucial for the high affinity of the VEGF-A165 terminal arginine with its NRP1 binding pocket, are depicted as yellow and light pink dots, respectively. (b) Superposition of NRP1 crystal structure complexes with VEGF-A165 (PDB ID: 4DEQ) [38] and SARS-CoV-2 (PDB ID: 7JJC) [37] CendR terminal residues bound into the NRP1 arginine binding pocket, yielding the comparison of the ligand-binding modes. VEGF-A165-NRP-1 complex is presented in orange cartoon and SARS-CoV-2 CendR-NRP-1 complex in green cartoon. NRP1 amino acid residues, significant for forming hydrogen bonds with the terminal arginine, are depicted as sticks of corresponding colours. Hydrogen bonding and salt bridge interactions are shown as yellow and light pink dots, respectively.

Figure 1

A general structural composition of NRP1 and NRP2 domains and the main NRP-mediated biological responses. The a1/a2 domain, presented in blue circles, is homologous to CUB (for complement C1r/C1s, Uegf, Bmp1); the b1/b2 domain, presented in green squares, is homologous to blood coagulation factor V/VIII domains; and the c domain, presented as an orange ellipse is homologous to meprin, A5, and μ-phosphatase (MAM). The intracellular PDZ domain is represented as a yellow square. Endogenous ligands of the VEGF family bind to the b1/b2 domains, while SEMA3s bind to the a1/a2/b1 domains [1,3]. (a) VEGFs form a complex with NRP and VEGFR that activates signalling pathways involved in angiogenesis associated with cancer [3,8]. (b) SEMA3s form a complex with NRP and plexin to activate signalling pathways that regulate axonal guidance and the immune, respiratory, and cardiovascular system as well as tumour cell responses [3,8,9].

Figure 3

Natural compound SEMA3A inhibitors.