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.