Herbal Immune-boosters: Substantial Warriors of Pandemic Covid-19 Battle

Discovery of naturally occurring inhibitors against SARS-CoV-2 3CL pro from Ginkgo biloba leaves via large-scale screening.

Abstract The main proteases (Mpro), also termed 3‐chymotrypsin‐like proteases (3CLpro), are a class of highly conserved cysteine hydrolases in β‐coronaviruses. Increasing evidence has demonstrated that 3CLpros play an indispensable role in viral replication and have been recognized as key targets for preventing and treating coronavirus‐caused infectious diseases, including COVID‐19. This review is focused on the structural features and biological function of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) main protease Mpro (also known as 3CLpro), as well as recent advances in discovering and developing SARS‐CoV‐2 3CLpro inhibitors. To better understand the characteristics of SARS‐CoV‐2 3CLpro inhibitors, the inhibition activities, inhibitory mechanisms, and key structural features of various 3CLpro inhibitors (including marketed drugs, peptidomimetic, and non‐peptidomimetic synthetic compounds, as well as natural compounds and their derivatives) are summarized comprehensively. Meanwhile, the challenges in this field are highlighted, while future directions for designing and developing efficacious 3CLpro inhibitors as novel anti‐coronavirus therapies are also proposed. Collectively, all information and knowledge presented here are very helpful for understanding the structural features and inhibitory mechanisms of SARS‐CoV‐2 3CLpro inhibitors, which offers new insights or inspiration to medicinal chemists for designing and developing more efficacious 3CLpro inhibitors as novel anti‐coronavirus agents.

The SARS‐CoV‐2 main protease (Mpro): Structure, function, and emerging therapies for COVID‐19

The novel coronavirus (SARS-CoV-2) causing COVID-19 disease pandemic has infected millions of people and caused more than thousands of deaths in many countries across the world. The number of infected cases is increasing day by day. Unfortunately, we do not have a vaccine and specific treatment for it. Along with the protective measures, respiratory and/or circulatory supports and some antiviral and retroviral drugs have been used against SARS-CoV-2, but there are no more extensive studies proving their efficacy. In this study, the latest publications in the field have been reviewed, focusing on the modulatory effects on the immunity of some natural antiviral dietary supplements, vitamins and minerals. Findings suggest that several dietary supplements, including black seeds, garlic, ginger, cranberry, orange, omega-3 and -6 polyunsaturated fatty acids, vitamins (e.g., A, B vitamins, C, D, E), and minerals (e.g., Cu, Fe, Mg, Mn, Na, Se, Zn) have anti-viral effects. Many of them act against various species of respiratory viruses, including severe acute respiratory syndrome-related coronaviruses. Therefore, dietary supplements, including vitamins and minerals, probiotics as well as individual nutritional behaviour can be used as adjuvant therapy together with antiviral medicines in the management of COVID-19 disease.

Dietary supplements, vitamins and minerals as potential interventions against viruses: Perspectives for COVID-19.

The aggregation and accumulation of amyloid-β plaques and tau proteins in the brain have been central characteristics in the pathophysiology of Alzheimer’s disease (AD), making them the focus of most of the research exploring potential therapeutics for this neurodegenerative disease. With success in interventions aimed at depleting amyloid-β peptides being limited at best, a greater understanding of the physiological role of amyloid-β peptides is needed. The development of amyloid-β plaques has been determined to occur 10–20 years prior to AD symptom manifestation, hence earlier interventions might be necessary to address presymptomatic AD. Furthermore, recent studies have suggested that amyloid-β peptides may play a role in innate immunity as an antimicrobial peptide. These findings, coupled with the evidence of pathogens such as viruses and bacteria in AD brains, suggests that the buildup of amyloid-β plaques could be a response to the presence of viruses and bacteria. This has led to the foundation of the antimicrobial hypothesis for AD. The present review will highlight the current understanding of amyloid-β, and the role of bacteria and viruses in AD, and will also explore the therapeutic potential of antimicrobial and antiviral drugs in Alzheimer’s disease.

The Use of Antimicrobial and Antiviral Drugs in Alzheimer’s Disease

Ginkgolic acids (GA) are alkylphenol constituents of the leaves and fruits of Ginkgo biloba. GA has shown pleiotropic effects in vitro, including: antitumor effects through inhibition of lipogenesis; decreased expression of invasion associated proteins through AMPK activation; and potential rescue of amyloid-β (Aβ) induced synaptic impairment. GA was also reported to have activity against Escherichia coli and Staphylococcus aureus. Several mechanisms for this activity have been suggested including: SUMOylation inhibition; blocking formation of the E1-SUMO intermediate; inhibition of fatty acid synthase; non-specific SIRT inhibition; and activation of protein phosphatase type-2C. Here we report that GA inhibits Herpes simplex virus type 1 (HSV-1) by inhibition of both fusion and viral protein synthesis. Additionally, we report that GA inhibits human cytomegalovirus (HCMV) genome replication and Zika virus (ZIKV) infection of normal human astrocytes (NHA). We show a broad spectrum of fusion inhibition by GA of all three classes of fusion proteins including HIV, Ebola virus (EBOV), influenza A virus (IAV) and Epstein Barr virus (EBV). In addition, we show inhibition of a non-enveloped adenovirus. Our experiments suggest that GA inhibits virion entry by blocking the initial fusion event. Data showing inhibition of HSV-1 and CMV replication, when GA is administered post-infection, suggest a possible secondary mechanism targeting protein and DNA synthesis. Thus, in light of the strong effect of GA on viral infection, even after the infection begins, it may potentially be used to treat acute infections (e.g. Coronavirus, EBOV, ZIKV, IAV and measles), and also topically for the successful treatment of active lesions (e.g. HSV-1, HSV-2 and varicella-zoster virus (VZV)).

Ginkgolic acid inhibits fusion of enveloped viruses.

Viral pathogens often exploit host cell regulatory and signaling pathways to ensure an optimal environment for growth and survival. Several studies have suggested that 5′-adenosine monophosphate-activated protein kinase (AMPK), an intracellular serine/threonine kinase, plays a significant role in the modulation of infection. Traditionally, AMPK is a key energy regulator of cell growth and proliferation, host autophagy, stress responses, metabolic reprogramming, mitochondrial homeostasis, fatty acid β-oxidation and host immune function. In this review, we highlight the modulation of host AMPK by various viruses under physiological conditions. These intracellular pathogens trigger metabolic changes altering AMPK signaling activity that then facilitates or inhibits viral replication. Considering the COVID-19 pandemic, understanding the regulation of AMPK signaling following infection can shed light on the development of more effective therapeutic strategies against viral infectious diseases.

https://www.mdpi.com/2073-4409/10/5/1118/pdf

Multifaceted role of AMPK in viral infections

Epstein-Barr virus (EBV) is typically found in a latent, asymptomatic state in immunocompetent individuals. Perturbations of the host immune system can stimulate viral reactivation. Furthermore, there are a myriad of EBV-associated illnesses including various cancers, post-transplant lymphoproliferative disease, and autoimmune conditions. A thorough understanding of this virus, and the interplay between stress and the immune system, is essential to establish effective treatment. This review will provide a summary of the interaction between both psychological and cellular stressors resulting in EBV reactivation. It will examine mechanisms by which EBV establishes and maintains latency and will conclude with a brief overview of treatments targeting EBV.

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Stress-Induced Epstein-Barr Virus Reactivation

Herpes simplex virus type 1 (HSV-1) causes a lifelong latent infection with an estimated global prevalence of 66%. Primary and recurrent HSV infections are characterized by a tingling sensation, followed by an eruption of vesicles, which can cause painful erosions. Commonly used antiviral drugs against HSV infection are nucleoside analogues including acyclovir (ACV), famciclovir, and valacyclovir. Although these nucleoside analogues reduce morbidity and mortality in immunocompetent individuals, ACV-resistant HSV strains (ACVR-HSV) have been isolated from immunocompromised patients. Thus, ACVR-HSV infection poses a critical emerging public health concern. Recently, we reported that ginkgolic acid (GA) inhibits HSV-1 by disrupting viral structure, blocking fusion, and inhibiting viral protein synthesis. Additionally, we showed GA affords a broad spectrum of fusion inhibition of all three classes of fusion proteins, including those of HIV, Ebola, influenza A and Epstein Barr viruses. Here we report GA’s antiviral activity against HSV-1 skin infection in BALB/cJ mice. GA-treated mice demonstrated a significantly reduced mortality rate and decreased infection scores compared to controls treated with dimethylsulfoxide (DMSO)-vehicle. Furthermore, GA efficiently inhibited ACVR-HSV-1 strain 17+ in vitro and in vivo. Since GA’s mechanism of action includes virucidal activity and fusion inhibition, it is expected to work alone or synergistically with other anti-viral drugs, and we anticipate it to be effective against additional cutaneous and potentially systemic viral infections.

Ginkgolic Acid Inhibits Herpes Simplex Virus Type 1 Skin Infection and Prevents Zosteriform Spread in Mice.

The human immune system boasts a diverse array of strategies for recognizing and eradicating invading pathogens. Human betaherpesviruses, a highly prevalent subfamily of viruses, include human cytomegalovirus (HCMV), human herpesvirus (HHV) 6A, HHV-6B, and HHV-7. These viruses have evolved numerous mechanisms for evading the host response. In this review, we will highlight the complex interplay between betaherpesviruses and the human immune response, focusing on protein function. We will explore methods by which the immune system first responds to betaherpesvirus infection as well as mechanisms by which viruses subvert normal cellular functions to evade the immune system and facilitate viral latency, persistence, and reactivation. Lastly, we will briefly discuss recent advances in vaccine technology targeting betaherpesviruses. This review aims to further elucidate the dynamic interactions between betaherpesviruses and the human immune system.

Maimoona S Bhutta

Papers

Ginkgolic acid inhibits fusion of enveloped viruses.

Multifaceted role of AMPK in viral infections

Stress-Induced Epstein-Barr Virus Reactivation

Ginkgolic Acid Inhibits Herpes Simplex Virus Type 1 Skin Infection and Prevents Zosteriform Spread in Mice.

Evasion of the Host Immune Response by Betaherpesviruses.