When NO^. Is not Enough: Chemical Systems, Advances and Challenges in the Development of NO^. and HNO Donors for Old and Current Medical Issues

Abstract

Nitric oxide (NO.) has been widely studied as an active agent of many physiological and pathological processes. Currently, NO. divides attention with its sibling molecule, nitroxyl (HNO), mainly due to their differences in physiological responses broadening their applications. In order for NO. and HNO to have their multiple biological effects, they must reach quite specific concentrations in the body. This key issue makes it essential to develop strategies for delivering these molecules in a controlled and selective manner. The wide range of activities of these compounds along with smart strategies in the development of NO./HNO donors have made them a hot spot. There are some NO. donor strategies in clinical use and also others in clinical trial, while HNO donors are further behind, illustrating the opportunities to come. Along these lines, we reviewed some current exciting NO. and HNO donor species, including organic‐ and inorganic‐based compounds, as well as nanomaterial platforms and NO. donor devices. This update may provide an overview of the systems currently available and how far we have come to meet multiple pharmacological needs.

Heme-Based Gas Sensors in Nature and Their Chemical and Biotechnological Applications

“…The first heme-based gas sensor discovered, sGC, has many physiological roles in humans, making it a very desirable drug target for the treatment of endothelial, cardiovascular and pulmonary disorders [93,94]. A series of nitric oxide (NO) donors was earlier employed targeting sGC, even before this sensor was known or this small molecule (NO) found to be biologically active.…”

“…The binding of NO to sGC strongly stimulates its cyclase activity, converting GTP into cGMP [27]. This is one of the reasons for the development of NO donor molecules, which can be employed to lower blood pressure, hypertension crisis, angina pectoris, glaucoma, among other applications [94]. However, the lack of selectivity and acquired tolerance to NO can limit its action in continuous use.…”

“…However, the lack of selectivity and acquired tolerance to NO can limit its action in continuous use. Some strategies have emerged to deal with these issues, particularly providing more selective delivery strategies either by using light, nanoparticles or other stimuli [1,94]. At the same time, other small molecules have been investigated, starting with YC-1, the first direct sGC stimulator discovered [95].…”

“…At the same time, other small molecules have been investigated, starting with YC-1, the first direct sGC stimulator discovered [95]. Currently, there are many organic-and inorganic-based molecules investigated as sGC stimulators or activators likely able to treat many conditions [92][93][94]96]. Two drugs (riociguat, 2013, and vericiguat, 2021) that function by targeting sGC are already approved for clinical use, opening many opportunities.…”

“…Among these systems, there are heme-based gas sensor proteins as potential drug targets [1,92]. In certain cases, the use of NO donors can be beneficial to assist with the elimination of the bacterial infection through interaction with heme-based gas sensors [94]. One of the major obstacles to eliminate bacteria is caused by the production of biofilm that leads to antibiotic tolerance [99].…”