Discovery of a new generation of angiotensin receptor blocking drugs:Receptor mechanisms and in silico binding to enzymes relevant to SARS-CoV-2

The discovery and facile synthesis of a new class of sartan-like arterial antihypertensive drugs (angiotensin receptor blockers [ARBs]), subsequently referred to as “bisartans” is reported. In vivo results and complementary molecular modelling presented in this communication indicate bisartans may be beneficial for the treatment of not only heart disease, diabetes, renal dysfunction, and related illnesses, but possibly COVID-19. Bisartans are novel bis-alkylated imidazole sartan derivatives bearing dual symmetric anionic biphenyl tetrazole moieties. In silico docking and molecular dynamics studies revealed bisartans exhibited higher binding affinities for the ACE2/spike protein complex (PDB 6LZG) compared to all other known sartans. They also underwent stable docking to the Zn2+ domain of the ACE2 catalytic site as well as the critical interfacial region between ACE2 and the SARS-CoV-2 receptor binding domain. Additionally, semi-stable docking of bisartans at the arginine-rich furin-cleavage site of the SARS-CoV-2 spike protein (residues 681–686) required for virus entry into host cells, suggest bisartans may inhibit furin action thereby retarding viral entry into host cells. Bisartan tetrazole groups surpass nitrile, the pharmacophoric “warhead” of PF-07321332, in its ability to disrupt the cysteine charge relay system of 3CLpro. However, despite the apparent targeting of multifunctional sites, bisartans do not inhibit SARS-CoV-2 infection in bioassays as effectively as PF-07321332 (Paxlovid)

Significance of Catecholamine Biosynthetic/Metabolic Pathway in SARS-CoV-2 Infection and COVID-19 Severity

The SARS-CoV-2 infection was previously associated with the expression of the dopamine biosynthetic enzyme L-Dopa decarboxylase (DDC). Specifically, a negative correlation was detected between DDC mRNA and SARS-CoV-2 RNA levels in in vitro infected epithelial cells and the nasopharyngeal tissue of COVID-19 patients with mild/no symptoms. However, DDC, among other genes related to both DDC expression and SARS-CoV-2-infection (ACE2, dACE2, EPO), was upregulated in these patients, possibly attributed to an orchestrated host antiviral response. Herein, by comparing DDC expression in the nasopharyngeal swab samples of severe/critical to mild COVID-19 cases, we showed a 20 mean-fold reduction, highlighting the importance of the expression of this gene as a potential marker of COVID-19 severity. Moreover, we identified an association of SARS-CoV-2 infection with the expression of key catecholamine biosynthesis/metabolism-related genes, in whole blood samples from hospitalized patients and in cultured cells. Specifically, viral infection downregulated the biosynthetic part of the dopamine pathway (reduction in DDC expression up to 7.5 mean-fold), while enhanced the catabolizing part (increase in monoamine oxidases A and B expression up to 15 and 10 mean-fold, respectively) in vivo, irrespectively of the presence of comorbidities. In accordance, dopamine levels in the sera of severe cases were reduced (up to 3.8 mean-fold). Additionally, a moderate positive correlation between DDC and MAOA mRNA levels (r = 0.527, p < 00001) in the blood was identified upon SARS-CoV-2-infection. These observations were consistent to the gene expression data from SARS-CoV-2-infected Vero E6 and A549 epithelial cells. Furthermore, L-Dopa or dopamine treatment of infected cells attenuated the virus-derived cytopathic effect by 55% and 59%, respectively. The SARS-CoV-2 mediated suppression of dopamine biosynthesis in cell culture was, at least in part, attributed to hypoxia-like conditions triggered by viral infection. These findings suggest that L-Dopa/dopamine intake may have a preventive or therapeutic value for COVID-19 patients

Neurorehabilitation Through Synergistic Man-Machine Interfaces Promoting Dormant Neuroplasticity in Spinal Cord Injury: Protocol for a Nonrandomized Controlled Trial

Background: Spinal cord injury (SCI) constitutes a major sociomedical problem, impacting approximately 0.32-0.64 million people each year worldwide; particularly, it impacts young individuals, causing long-term, often irreversible disability. While effective rehabilitation of patients with SCI remains a significant challenge, novel neural engineering technologies have emerged to target and promote dormant neuroplasticity in the central nervous system. Objective: This study aims to develop, pilot test, and optimize a platform based on multiple immersive man-machine interfaces offering rich feedback, including (1) visual motor imagery training under high-density electroencephalographic recording, (2) mountable robotic arms controlled with a wireless brain-computer interface (BCI), (3) a body-machine interface (BMI) consisting of wearable robotics jacket and gloves in combination with a serious game (SG) application, and (4) an augmented reality module. The platform will be used to validate a self-paced neurorehabilitation intervention and to study cortical activity in chronic complete and incomplete SCI at the cervical spine. Methods: A 3-phase pilot study (clinical trial) was designed to evaluate the NeuroSuitUp platform, including patients with chronic cervical SCI with complete and incomplete injury aged over 14 years and age-/sex-matched healthy participants. Outcome measures include BCI control and performance in the BMI-SG module, as well as improvement of functional independence, while also monitoring neuropsychological parameters such as kinesthetic imagery, motivation, self-esteem, depression and anxiety, mental effort, discomfort, and perception of robotics. Participant enrollment into the main clinical trial is estimated to begin in January 2023 and end by December 2023. Results: A preliminary analysis of collected data during pilot testing of BMI-SG by healthy participants showed that the platform was easy to use, caused no discomfort, and the robotics were perceived positively by the participants. Analysis of results from the main clinical trial will begin as recruitment progresses and findings from the complete analysis of results are expected in early 2024. Conclusions: Chronic SCI is characterized by irreversible disability impacting functional independence. NeuroSuitUp could provide a valuable complementary platform for training in immersive rehabilitation methods to promote dormant neural plasticity