Zn2+ and Cu2+ Interaction with the Recognition Interface of ACE2 for SARS-CoV-2 Spike Protein.

The spike protein (S) of SARS-CoV-2 is able to bind to the human angiotensin-converting enzyme 2 (ACE2) receptor with a much higher affinity compared to other coronaviruses. The binding interface between the ACE2 receptor and the spike protein plays a critical role in the entry mechanism of the SARS-CoV-2 virus. There are specific amino acids involved in the interaction between the S protein and the ACE2 receptor. This specificity is critical for the virus to establish a systemic infection and cause COVID-19 disease. In the ACE2 receptor, the largest number of amino acids playing a crucial role in the mechanism of interaction and recognition with the S protein is located in the C-terminal part, which represents the main binding region between ACE2 and S. This fragment is abundant in coordination residues such as aspartates, glutamates, and histidine that could be targeted by metal ions. Zn2+ ions bind to the ACE2 receptor in its catalytic site and modulate its activity, but it could also contribute to the structural stability of the entire protein. The ability of the human ACE2 receptor to coordinate metal ions, such as Zn2+, in the same region where it binds to the S protein could have a crucial impact on the mechanism of recognition and interaction of ACE2-S, with consequences on their binding affinity that deserve to be investigated. To test this possibility, this study aims to characterize the coordination ability of Zn2+, and also Cu2+ for comparison, with selected peptide models of the ACE2 binding interface using spectroscopic and potentiometric techniques.

Traditional Chinese Medicine as the preventive and therapeutic remedy for COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic still has tremendous impacts on the global socio-economy and quality of living. The traditional Chinese Medicines (TCM) approach showed encouraging results during previous outbreaks of Severe Acute Respiratory Syndrome-related coronavirus (SARS-CoV) and the Middle East Respiratory Syndrome Coronavirus (MERS-CoV). With limited treatment availability, TCM herbs and formulations could be viable to reduce COVID-19 symptoms and potential sources for discovering novel therapeutic targets. We reviewed 12 TCM herbs and formulations recommended for COVID-19 management by the National Health Commission and National Administration of Traditional Chinese Medicine, the People's Republic of China. This article explored the Chinese national authorities' guidelines from 2003 to 2020, the scientific data in public databases for the recommended TCM remedies, and their potential mechanistic actions in COVID-19 management. Several TCM herbs and formulations could potentially benefit COVID-19 management. The recommended TCM oral preparations list are Huoxiang zhengqi, Jinhua Qinggan, Lianhua Qingwen, and Shufeng jiedu; the recommended injection preparations comprise Xiyanping Xuebijing, Re-Du-Ning, Tanreqing, Xingnaojing, Shenfu, Shengmai, and Shenmai. TCM remedies are viable options for symptom alleviation and management of COVID-19. The current SARS-CoV-2 pandemic presents an opportunity to find novel therapeutic targets from TCM-active ingredients. Despite the recommendations in Chinese National guidelines, these remedies warrant further assessments in well-designed clinical trials for their efficacies in COVID-19.

Structural modeling of protein ensembles between E3 RING ligases and SARS-CoV-2: The role of zinc binding domains.

BACKGROUND: The ubiquitin system is a modification process with many different cellular functions including immune signaling and antiviral functions. E3 ubiquitin ligases are enzymes that recruit an E2 ubiquitin-conjugating enzyme bound to ubiquitin in order to catalyze the transfer of ubiquitin from the E2 to a protein substrate. The RING E3s, the most abundant type of ubiquitin ligases, are characterized by a zinc (II)-binding domain called RING (Really Interesting New Gene). Viral replication requires modifying and hijacking key cellular pathways within host cells such as cellular ubiquitination. There are well-established examples where a viral proteins bind to RING E3s, redirecting them to degrade otherwise long-lived host proteins or inhibiting E3's ubiquitination activity. Recently, three binary interactions between SARS-CoV-2 proteins and innate human immune signaling Ε3 RING ligases: NSP15-RNF41, ORF3a-TRIM59 and NSP9-MIB1 have been experimentally established. METHODS: In this work, we have investigated the mode of the previous experimentally supported NSP15-RNF41, ORF3a,-TRIM59 and NSP9-MIB1 binary interactions by in silico methodologies intending to provide structural insights of E3-virus interplay that can help identify potential inhibitors that could block SARS-CoV-2 infection of immune cells. CONCLUSION: In silico methodologies have shown that the above human E3 ligases interact with viral partners through their Zn(II) binding domains. This RING mediated formation of stable SARS-CoV-2-E3 complexes indicates a critical structural role of RING domains in immune system disruption by SARS-CoV-2-infection. DATA AVAILABILITY: The data used to support the findings of this research are included within the article and are labeled with references.

Structural modeling of protein ensembles between E3 RING ligases and SARS-CoV-2: the role of zinc binding domains

Background The ubiquitin system is a modification process with many different cellular functions including immune signaling and antiviral functions. E3 ubiquitin ligases are enzymes that recruit an E2 ubiquitin-conjugating enzyme bound to ubiquitin in order to catalyze the transfer of ubiquitin from the E2 to a protein substrate. The RING E3s, the most abundant type of ubiquitin ligases, are characterized by a zinc (II)-binding domain called RING (Really Interesting New Gene). Viral replication requires modifying and hijacking key cellular pathways within host cells such as cellular ubiquitination. There are well-established examples where a viral proteins bind to RING E3s, redirecting them to degrade otherwise long-lived host proteins or inhibiting E3’s ubiquitination activity. Recently, three binary interactions between SARS-CoV-2 proteins and innate human immune signaling Ε3 RING ligases: NSP15-RNF41, ORF3a-TRIM59 and NSP9-MIB1 have been experimentally established. Methods In this work, we have investigated the mode of the previous experimentally supported NSP15-RNF41, ORF3a,-TRIM59 and NSP9-MIB1 binary interactions by in silico methodologies intending to provide structural insights of E3-virus interplay that can help identify potential inhibitors that could block SARS-CoV-2 infection of immune cells. Conclusion In silico methodologies have shown that the above human E3 ligases interact with viral partners through their Zn(II) binding domains. This RING mediated formation of stable SARS-CoV-2-E3 complexes indicates a critical structural role of RING domains in immune system disruption by SARS-CoV-2-infection. Data Availability The data used to support the findings of this research are included within the article and are labeled with references. Graphical

Quercetin in the Prevention and Treatment of Coronavirus Infections: A Focus on SARS-CoV-2.

The COVID-19 outbreak seems to be the most dangerous challenge of the third millennium due to its highly contagious nature. Amongst natural molecules for COVID-19 treatment, the flavonoid molecule quercetin (QR) is currently considered one of the most promising. QR is an active agent against SARS and MERS due to its antimicrobial, antiviral, anti-inflammatory, antioxidant, and some other beneficial effects. QR may hold therapeutic potential against SARS-CoV-2 due to its inhibitory effects on several stages of the viral life cycle. In fact, QR inhibits viral entry, absorption, and penetration in the SARS-CoV virus, which might be at least partly explained by the ability of QR and its derivatives to inhibit 3-chymotrypsin-like protease (3CLpro) and papain-like protease (PLpro). QR is a potent immunomodulatory molecule due to its direct modulatory effects on several immune cells, cytokines, and other immune molecules. QR-based nanopreparations possess enhanced bioavailability and solubility in water. In this review, we discuss the prospects for the application of QR as a preventive and treatment agent for COVID-19. Given the multifactorial beneficial action of QR, it can be considered a very valid drug as a preventative, mitigating, and therapeutic agent of COVID-19 infection, especially in synergism with zinc, vitamins C, D, and E, and other polyphenols.

Individual risk management strategy for SARS-CoV-2 infection: A step toward personalized healthcare.

Lethal or critical COVID-19 occurs most in infected hosts with certain risk factors such as advanced age or pre-existing disease. Host metabolic status significantly affects the clinical presentations of SARS-CoV-2 infection. Individual risk management is thus crucial for preventing severe COVID-19. Such susceptibility is individual, depending on a multitude of factors. Personalized risk assessment requires the inclusive analysis of big health data to stratify individual risk and derive a customized action plan. Personalized medicine requires shifting from the virology aspect per se to the whole individual's consideration, including dietary pattern, nutritional status, supporting lifestyle, co-existing diseases, and environmental factors. In this short communication, we discuss the individual management strategy for SARS-CoV2 infection as a step towards future personalized healthcare.

The microbiota-mediated dietary and nutritional interventions for COVID-19.

Worldwide, scientists are looking for specific treatment for COVID-19. Apart from the antiviral approach, the interventions to support healthy immune responses to the virus are feasible through diet, nutrition, and lifestyle approaches. This narrative review explores the recent studies on dietary, nutritional, and lifestyle interventions that influence the microbiota-mediated immunomodulatory effects against viral infections. Cumulative studies reported that the airway microbiota and SARS-CoV-2 leverage each other and determine the pathogen-microbiota-host responses. Cigarette smoking can disrupt microbiota abundance. The composition and diversification of intestinal microbiota influence the airway microbiota and the innate and adaptive immunity, which require supports from the balance of macro- and micronutrients from the diet. Colorful vegetables supplied fermentable prebiotics and anti-inflammatory, antioxidant phytonutrients. Fermented foods and beverages support intestinal microbiota. In sensitive individuals, the avoidance of the high immunoreactive food antigens contributes to antiviral immunity. This review suggests associations between airway and intestinal microbiota, antiviral host immunity, and the influences of dietary, nutritional, and lifestyle interventions to prevent the clinical course toward severe COVID-19.

A SARS-CoV-2 -human metalloproteome interaction map.

The recent pandemic caused by the novel coronavirus resulted in the greatest global health crisis since the Spanish flu pandemic of 1918. There is limited knowledge of whether SARS-CoV-2 is physically associated with human metalloproteins. Recently, high-confidence, experimentally supported protein-protein interactions between SARS-CoV-2 and human proteins were reported. In this work, 58 metalloproteins among these human targets have been identified by a structure-based approach. This study reveals that most human metalloproteins interact with the recently discovered SARS-CoV-2 orf8 protein, whose antibodies are one of the principal markers of SARS-CoV-2 infections. Furthermore, this work provides sufficient evidence to conclude that Zn2+ plays an important role in the interplay between the novel coronavirus and humans. First, the content of Zn-binding proteins in the involved human metalloproteome is significantly higher than that of the other metal ions. Second, a molecular linkage between the identified human Zn-binding proteome with underlying medical conditions, that might increase the risk of severe illness from the SARS-CoV-2 virus, has been found. Likely perturbations of host cellular metal homeostasis by SARS-CoV-2 infection are highlighted.

The Role of Diet and Supplementation of Natural Products in COVID-19 Prevention.

Recently, a discussion has begun on the global management strategy against COVID-19 based on the hypothesis that individuals' macro- and micronutrient status combined with antiviral drugs and herbs can be an ally against the infection. The hypothesis is that people's nutritional and oxidative scavenging capacity may provide fundamental data to predict severe and acute pulmonary distress following SARS-Cov2 infection. Consequently, the scientific community has addressed the role of balanced diets, nutritional supplements, and micronutrients, including folk herbal formulations, in reducing hospitalization and the severity of pulmonary impact in COVID-19 by preventing the most serious forms of the infection. This led to an animated debate on the potential effectiveness of some vitamins, micronutrients, and traditional Chinese medicine in preventing COVID-19, with some authors convinced that plant extracts could act oppositely, exacerbating the effect of the infection. While current research is still far to assess the suggestions and issues raised in this short communication, it is undoubtedly true that determining an individual's current metabolic status, including macro- and micronutrients, is an essential factor in defining any individuals' deficiencies, which will need to be addressed urgently through a proper diet, specific personalized nutritional supplementation, and lifestyle changes.

Chloroquine and hydroxychloroquine in the treatment of COVID-19: the never-ending story.

The anti-malarial drugs chloroquine (CQ) and hydroxychloroquine (HCQ) have been suggested as promising agents against the new coronavirus SARS-CoV-2 that induces COVID-19 and as a possible therapy for shortening the duration of the viral disease. The antiviral effects of CQ and HCQ have been demonstrated in vitro due to their ability to block viruses like coronavirus SARS in cell culture. CQ and HCQ have been proposed to reduce immune reactions to infectious agents, inhibit pneumonia exacerbation, and improve lung imaging investigations. CQ analogs have also revealed the anti-inflammatory and immunomodulatory effects in treating viral infections and related ailments. There was, moreover, convincing evidence from early trials in China about the efficacy of CQ and HCQ in the anti-COVID-19 procedure. Since then, research and studies have been massive to ascertain these drugs' efficacy and safety in treating the viral disease. In the present review, we construct a synopsis of the main properties and current data concerning the metabolism of CQ/HCQ, which were the basis of assessing their potential therapeutic roles against the new coronavirus infection. The effective role of QC and HCQ in the prophylaxis and therapy of COVID-19 infection is discussed in light of the latest international medical-scientific research results. KEY POINTS: • Data concerning metabolism and properties of CQ/HCQ are discussed. • The efficacy of CQ/HCQ against COVID-19 has been the subject of contradictory results. • CQ/HCQ has little or no effect in reducing mortality in SARS-CoV-2-affected patients.

Interrelations between COVID-19 and other disorders.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a respiratory tract virus that causes Coronavirus disease (COVID-19). The virus originated in Wuhan, China, in December 2019 and has spread across the globe to-date. The disease ranges from asymptomatic carriers to symptoms such as fever, sore throat, cough, lung infections, and in severe cases, acute respiratory distress syndrome, sepsis, and death. As many as 50% of patients reported having at least one comorbidities with COVID-19 upon hospital admission. Hypertension, diabetes, chronic obstructive pulmonary disease, obesity, and cardiovascular diseases are among the most commonly reported. Comorbidities are contributing to acute disease prognosis and increased risk of severe symptoms. Around 70% of patients who require ICU care have been observed to have comorbidities. This review intends to understand how some of these comorbidities affect the disease's prognosis and how severe the outcome can be expected.

Micronutrients as immunomodulatory tools for COVID-19 management.

COVID-19 rapidly turned to a global pandemic posing lethal threats to overwhelming health care capabilities, despite its relatively low mortality rate. The clinical respiratory symptoms include dry cough, fever, anosmia, breathing difficulties, and subsequent respiratory failure. No known cure is available for COVID-19. Apart from the anti-viral strategy, the supports of immune effectors and modulation of immunosuppressive mechanisms is the rationale immunomodulation approach in COVID-19 management. Diet and nutrition are essential for healthy immunity. However, a group of micronutrients plays a dominant role in immunomodulation. The deficiency of most nutrients increases the individual susceptibility to virus infection with a tendency for severe clinical presentation. Despite a shred of evidence, the supplementation of a single nutrient is not promising in the general population. Individuals at high-risk for specific nutrient deficiencies likely benefit from supplementation. The individual dietary and nutritional status assessments are critical for determining the comprehensive actions in COVID-19.

Arsenic intoxication: general aspects and chelating agents.

Arsenic (As) is widely used in the modern industry, especially in the production of pesticides, herbicides, wood preservatives, and semiconductors. The sources of As such as contaminated water, air, soil, but also food, can cause serious human diseases. The complex mechanism of As toxicity in the human body is associated with the generation of free radicals and the induction of oxidative damage in the cell. One effective strategy in reducing the toxic effects of As is the usage of chelating agents, which provide the formation of inert chelator-metal complexes with their further excretion from the body. This review discusses different aspects of the use of metal chelators, alone or in combination, in the treatment of As poisoning. Consideration is given to the therapeutic effect of thiol chelators such as meso-2,3-dimercaptosuccinic acid, sodium 2,3-dimercapto-1-propanesulfonate, 2,3-dimercaptopropanol, penicillamine, ethylenediaminetetraacetic acid, and other recent agents against As toxicity. The review also considers the possible role of flavonoids, trace elements, and herbal drugs as promising natural chelating and detoxifying agents.