New opportunities for the application of natural products based on nitric oxide modulation: From research to registered patents

Abstract Nitric oxide (NO) has an essential role in endothelial function and, besides its well-established vasodilating propriety, it is involved in several biological processes, including neurotransmission and cellular immunity. NO is endogenously produced by four different isoforms of nitric oxide synthase (NOS): the neuronal (nNOS), the endothelial (eNOS), the inducible isoform (iNOS), and the new isoform responsible for the NO production in the mitochondria (mtNOS). In past years, a growing body of evidence has been implicating an abnormal NO signaling in a variety of pathological conditions, most of them related to the cardiovascular system but also to cancer, neurodegenerative diseases, inflammation, and even psychiatric disorders. Therefore, modulating NO pathway may be important for the treatment of several diseases, which makes this pathway a potential target for new drug development. Some strategies have been proposed to enhancing NO bioavailability, mainly acting on NOS cofactors or avoiding NO breakdown and, in this context, there are already different drugs that act on the NO downstream signaling targets. In the context of natural products, some compounds present in medicinal herbs, vegetables, fruits, soy, tea and red wine, have been shown to induce NO formation and, some of them, to suppress the induction of the inducible NOS in inflammation and infection. As an example, and a widely known medicinal herb, the ginseng, and its saponins ginsenosides have been shown to relax blood vessels (effect of ginseng as a blood pressure lowering) and corpus cavernosum, thus playing a possible role in the treatment of men who have erectile dysfunction. Here, we will discuss the potential therapeutic effects of some natural products, and their bioavailable constituents, metabolites, and crude extracts, on NO and NOS, in the context of different biological processes. Our focus is to summarize the central role of this molecule and identify further, or new perspectives, of natural products on modulating NO pathway. In the period of 1981–2014, of the 1562 medicines produced, approximately 70% were originated from natural products and their derivatives. In the period from 2005 to 2010, 19 drugs based on natural products were approved for marketing, among which seven are classified as natural products, 10 as semi-synthetic natural products and 2 as drugs derived from natural products. Additionally, this chapter will explore the most recent patents (2010–18) containing biomolecules in products and processes related to NO modulation deposited in the Espacenet, EPO and WIPO databases.