Dual inhibition of CB1 receptors and iNOS, as a potential novel approach to the pharmacological management of acute and long COVID-19

Abstract

COVID-19 (SARS-CoV-2) causes multiple inflammatory complications, resulting not only in severe lung inflammation but also harm to other organs. Although the current focus is on the management of acute COVID-19, there is growing concern about long-term effects of COVID-19 (Long Covid), such as fibroproliferative changes in the lung, heart and kidney. Therefore, the identification of therapeutic targets not only for the management of acute COVID-19 but also for preventing Long Covid are needed, and would mitigate against long-lasting health burden and economic costs, in addition to saving lives. COVID-19 induces pathological changes via multiple pathways, which could be targeted simultaneously for optimal effect. We discuss the potential pathologic function of increased activity of the endocannabinoid/CB₁ receptor system and inducible NO synthase (iNOS). We advocate a polypharmacology approach, wherein a single chemical entity simultaneously interacts with CB₁ receptors and iNOS causing inhibition, as a potential therapeutic strategy for COVID-19-related health complications. LINKED ARTICLES: This article is part of a themed issue on The second wave: are we any closer to efficacious pharmacotherapy for COVID 19? (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.10/issuetoc.

Keywords: COVID-19; SARS-CoV-2; iNOS inhibitor; peripheral CB1 antagonist; polypharmacology; pulmonary fibrosis.

FIGURE 1

Multi‐target therapeutic strategy for COVID‐19‐related multiple health complications by dual inhibition of CB₁ receptors and iNOS. (a) Dual inhibition of CB₁ receptors (CB₁R) and iNOS may not only attenuate acute COVID‐19 complications such as acute respiratory distress syndrome (ARDS), septicaemia, heart failure, acute kidney injury, endothelial dysfunction and thrombosis but may also mitigate the development of pulmonary fibrosis as a late sequela of COVID‐19. (b) Both CNR1 and NOS2 gene expression are increased in lungs of COVID‐19 patients. Lung expression profiles of CNR1 and NOS2 were retrieved from RNAseq data set (Desai et al., 2020) from five virus‐negative controls, seven COVID cases with low viral load and eight COVID cases with high viral load. Multiple data points obtained from different lung lobes were used for COVID cases considering temporal and spatial heterogeneity of host response to SARS‐CoV‐2 infection. The figure was generated in Biorender.com