Broadening COVID-19 Interventions to Drug Innovation: Neprilysin Pathway as a Friend, Foe, or Promising Molecular Target?

Abstract

The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus is anticipated to transition to an endemic state as vaccines are providing relief in some, but not all, countries. Drug discovery for COVID-19 can offer another tool in the fight against the pandemic. Additionally, COVID-19 impacts multiple organs that call for a systems medicine approach to planetary health and therapeutics innovation. In this context, innovation for drugs that prevent and treat COVID-19 is timely and much needed. As the virus variants emerge under different ecological conditions and contexts in the long haul, a broad array of vaccine and drug options will be necessary. This expert review article argues for a need to expand the COVID-19 interventions, including and beyond vaccines, to stimulate discovery and development of novel medicines against SARS-CoV-2 infection. The Renin-Angiotensin-Aldosterone System (RAAS) is known to play a major role in SARS-CoV-2 infection. Neprilysin (NEP) and angiotensin-converting enzyme (ACE) have emerged as the pharmaceutical targets of interest in the search for therapeutic interventions against COVID-19. While the NEP/ACE inhibitors offer promise for repurposing against COVID-19, they may display a multitude of effects in different organ systems, some beneficial, and others adverse, in modulating the inflammation responses in the course of COVID-19. This expert review offers an analysis and discussion to deepen our present understanding of the pathophysiological function of neprilysin in multiple organs, and the possible effects of NEP inhibitor-induced inflammatory responses in COVID-19-infected patients.

Heterogeneity of neutrophils and inflammatory responses in patients with COVID-19 and healthy controls

“…Conversely, the mature neutrophil clusters had suppression of granule content genes, but distinct patterns of gene activation that were relatively low in the immature populations ( Figure 4C ). Clusters 2 and 8 displayed upregulation of MMP9, several S100A genes including S100A12, and MME (i.e., Neprilysin), which have been implicated in the pathogenesis of COVID-19 ( 37 , 38 ). Clusters 3, 5, and 6 had high levels of expression of regulatory genes for transcription and apoptosis ( Figure 4C ).…”

Extracellular vesicles and angiotensin-converting enzyme 2 in COVID-19 disease

“…A recent study reported that NEP inhibitor sacubitril can inhibit further cleavage of angiotensin 1-7 [17], and therefore, may favor the preservation of angiotensin 1-7 [17]. Studies have shown the beneficial effects of sacubitril on the regulation of angiotensin 1-7 and the improvement of outcomes of COVID-19 disease [15,17,[95][96][97]. Thus, several clinical trials using neprilysin inhibitor sacubitril have been proposed for the treatment of COVID-19 for a multitargeted therapeutic approach [15,98].…”

Роль Брадикініну В Розвитку COVID-19 Та Інших Захворювань

“…АПФ є ключовою кініназою ІІ, яка відщеплює С-кінцеві дипептиди від кінінів, що робить їх неактивними. Кініни розщеплюються по залишку внутрішнього фенілаланіну (Phe5 у БК) мембранозв'язаною нейтральною ендопептидазою (neutral endopeptidase, NEP) [23]. Таким чином, враховуючи цей консорціум перетравлюючих ферментів, тривалість перебування БK у циркуляції після його тимчасової активності відповідає лише кільком секундам [24].…”