Identification of Flavonoids as Potent Inhibitors Against MERS-CoV 3C-like Protease

In 2012, a coronavirus was isolated from a patient with severe pneumonia. This beta-coronavirus, which appeared in Saudi Arabia, was named Middle East Respiratory Syndrome Coro-navirus (MERS-CoV). MERS-CoV is the sixth identified coronavirus that has the ability to infect humans. The Middle East respiratory syndrome-coronavirus (MERS-CoV) is a zoonotic pathogen transmitted between animals and humans. To date, MERS-CoV is responsible for an epidemic that is still ongoing, but limited to the Arabian Peninsula, with a total number of more than 2000 cases identified and a mortality rate of around 35%. The largest outbreaks of human-to-human transmission were reported in Jeddah in 2014 and South Korea in 2015. This infection causes a high mortality rate and no vaccine or medical countermeasures are currently available. Currently, no specific treatment or vaccine is available against this virus. The current challenge is to contain the epidemic and continue research efforts to develop a vaccine and a treatment. Certain flavonoids inhibit the replication of viral RNA and have therapeutic potential against viruses and bacteria. Therefore, it is suggested that flavonoids with these characteristics can be used as models to develop potent inhibi-tors of MERS-CoV. This work reviews current knowledge and provides an update on MERS-CoV and MERS-CoV 3Clpro virology, epidemiology, clinical features, and the use of flavonoids as potential inhibitors and therapeutic agents for MERS-CoV, and MERS-CoV 3Clpro. This review tries to elucidate the structure-activity relationships (SAR) of varied polyphenols against MERS-CoV 3C-like protease (3Clpro).Copyright © 2022 Bentham Science Publishers.

Theoretical analysis of a measles model with nonlinear incidence functions

Measles is a highly contagious respiratory disease of global public health concern. A deterministic mathematical model for the transmission dynamics of measles in a population with Crowley–Martin incidence function to account for the inhibitory effect due to susceptible and infected individuals and vaccination is formulated and analyzed using standard dynamical systems methods. The basic reproduction number is computed. By constructing a suitable Lyapunov function, the disease-free equilibrium is shown to be globally asymptotically stable. Using the Center Manifold theory, the model exhibits a forward bifurcation, which implies that the endemic equilibrium is also globally asymptotically stable. To determine the optimal choice of intervention measures to mitigate the spread of the disease, an optimal control problem is formulated (by introducing a set of three time-dependent control variables representing the first and second vaccine doses, and the palliative treatment) and analyzed using Pontryagin's Maximum Principle. To account for the scarcity of measles vaccines during a major outbreak or other causes such as the COVID-19 pandemic, a Holling type-II incidence function is introduced at the model simulation stage. The control strategies have a positive population level impact on the evolution of the disease dynamics. Graphical results reveal that when the mass-action incidence function is used, the number of individuals who received first and second vaccine dose is smaller compared to the numbers when the Crowley–Martin incidence-type function is used. Inhibitory effect of susceptibles tends to have the same effect on the population level as the Crowley–Martin incidence function, while the control profiles when inhibitory effect of the infectives is considered have similar effect as when the mass-action incidence is used, or when there is limitation in the availability of measles vaccines. Missing out the second measles vaccine dose has a negative impact on the initial disease prevalence. © 2022 Elsevier B.V.

Natural Products with Tandem Anti-inflammatory, Immunomodulatory and Anti-SARS-CoV/2 Effects: A Drug Discovery Perspective against SARS-CoV-2.

BACKGROUND: COVID-19 is still causing long-term health consequences, mass deaths, and collapsing healthcare systems around the world. There are no efficient drugs for its treatment. However, previous studies revealed that SARS-CoV-2 and SARS-CoV have 96% and 86.5% similarities in cysteine proteases (3CLpro) and papain-like protease (PLpro) sequences, respectively. This resemblance could be important in the search for drug candidates with antiviral effects against SARS-CoV-2. OBJECTIVE: This paper is a compilation of natural products that inhibit SARS-CoV 3CLpro and PLpro and, concomitantly, reduce inflammation and/or modulate the immune system as a perspective strategy for COVID-19 drug discovery. It also presents in silico studies performed on these selected natural products using SARS-CoV-2 3CLpro and PLpro as targets to propose a list of hit compounds. METHODS: The plant metabolites were selected in the literature based on their biological activities on SARS-CoV proteins, inflammatory mediators, and immune response. The consensus docking analysis was performed using four different packages. RESULTS: Seventy-nine compounds reported in the literature with inhibitory effects on SARS-CoV proteins were reported as anti-inflammatory agents. Fourteen of them showed immunomodulatory effects in previous studies. Five and six of these compounds showed significant in silico consensus as drug candidates that can inhibit PLpro and 3CLpro, respectively. Our findings corroborated recent results reported on anti-SARS-CoV-2 in the literature. CONCLUSION: This study revealed that amentoflavone, rubranoside B, savinin, psoralidin, hirsutenone, and papyriflavonol A are good drug candidates for the search of antibiotics against COVID-19.