Pericytes may facilitate SARS-CoV-2 entry into the nervous system

Objective: Although the neurological and olfactory symptoms of coronavirus disease 2019 have been identified, the neurotropic properties of the causative virus, severe acute respiratory syndrome-associated coronavirus 2 (SARS-CoV-2), remain unknown. We sought to identify the susceptible cell types and potential routes of SARS-CoV-2 entry into the central nervous system, olfactory system, and respiratory system. Method(s): We collected single-cell RNA data from normal brain and nasal epithelium specimens, along with bronchial, tracheal, and lung specimens in public datasets. The susceptible cell types that express SARS-CoV-2 entry genes were identified using single-cell RNA sequencing and the expression of the key genes at protein levels was verified by immunohistochemistry. We compared the coexpression patterns of the entry receptor angiotensin-converting enzyme 2 (ACE2) and the spike protein priming enzyme transmembrane serine protease (TMPRSS)/cathepsin L among the specimens. Result(s): The SARS-CoV-2 entry receptor ACE2 and the spike protein priming enzyme TMPRSS/cathepsin L were coexpressed by pericytes in brain tissue;this coexpression was confirmed by immunohistochemistry. In the nasal epithelium, ciliated cells and sustentacular cells exhibited strong coexpression of ACE2 and TMPRSS. Neurons and glia in the brain and nasal epithelium did not exhibit coexpression of ACE2 and TMPRSS. However, coexpression was present in ciliated cells, vascular smooth muscle cells, and fibroblasts in tracheal tissue;ciliated cells and goblet cells in bronchial tissue;and alveolar epithelium type 1 cells, AT2 cells, and ciliated cells in lung tissue. Conclusion(s): Neurological symptoms in patients with coronavirus disease 2019 could be associated with SARS-CoV-2 invasion across the blood-brain barrier via pericytes. Additionally, SARS-CoV-2-induced olfactory disorders could be the result of localized cell damage in the nasal epithelium.Copyright © Wolters Kluwer Health, Inc. All rights reserved.

Mechanisms and implications of COVID-19 transport into neural tissue

The neuropathogenicity of COVID-19 was reported shortly after detection of the virus when patients began reporting symptoms of diminished taste and smell, headaches, mental status changes, and more. As the virus spread, increasing data on viral symptoms in conjunction with novel theories on COVID-19 virulence factors indicated that the virus had neurotropic properties. Several mechanisms have been proposed detailing severe acute respiratory syndrome coronavirus disease 2019 (SARS-CoV-2) transport past the blood–brain barrier and into neural tissue. This chapter offers a comprehensive review of possible neurotropic mechanisms including transport via the angiotensin-converting enzyme 2 (ACE-2) receptor, transportation directly past or through the blood–brain barrier, transsynaptic neuronal transfer, and olfactory conduction. © 2023 Elsevier Inc. All rights reserved.

Blood brain barrier disruption following COVID-19 infection and neurological manifestations

Neurological manifestations have been reported following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The presence of SARS-CoV-2 in brains of affected individuals has been documented. However, the exact route of entry into the brain and subsequent post-infection consequences are not fully understood. Blood–brain barrier (BBB) is an interface between systemic circulation and central nervous system (CNS) that strictly regulates entry of specific molecules from blood to the brain. The functional component of BBB is neurovascular unit (NVU) and any alterations in the structure or function of BBB is detrimental to the CNS functions. Evidence suggests that SARS-CoV-2 infection disrupts BBB integrity and functions directly or indirectly. This chapter highlights the likely mechanisms involved in entry of SARS-CoV-2 into the brain. Further, the alterations in BBB have been implicated in neurological symptoms observed in SARS-CoV-2 patients. Moreover, systemic inflammation and other peripheral factors post infection also contribute to the disruption of BBB. The key protein of SARS-CoV-2, spike protein (S1) induces significant alterations in BBB properties. Entry of S1 protein into brain triggers a proinflammatory cascade that affects BBB integrity. Therefore, understanding the pathophysiological mechanisms in BBB dysfunction and subsequent neurological manifestations along with long-term effects on brain particularly Alzheimer's disease (AD) following coronavirus disease 2019 (COVID-19) is of utmost importance. © 2023 Elsevier Inc. All rights reserved.

Long COVID, Music, Blood-Brain Barrier, and Nanomedicines

At the beginning of the first COVID-19 wave, it was believed that the life of the patients who had safely survived pulmonary complications caused by SARS-CoV-2 would soon return to normal. Today, we know that this is not for all patients the case. Unfortunately, for many patients, COVID-19 changed into Long COVID – not a life-threatening condition such as the short period of the infection with the coronavirus but with the potential to considerably reduce the quality of life. Notably, Long COVID manifests itself in major pathological alteration in the brain, besides other organs. It is unclear whether the alterations in the brain are reversible. Alterations include but are not limited to cognitive impairment and substantial reduction of grey matter. These clinical findings represent an urgent challenge for the design of nanomedicines targeting the brain and the mode of their application. The challenge comprises a third aspect, which is of physical nature and is the key to a revolution in nanomedicine: the blood-brain barrier (BBB). Even if a nanomedicine is effective in vitro, it remains therapeutically useless if it cannot cross the BBB, which safeguards that neither pathogens nor nanoparticles enter the best-protected organ in our body. Here, we present a theoretical model and discuss experimental results, which coherently indicate that it is possible to transiently open the BBB by its mechanical excitation and/or via chemical modification induced by music. © 2022, Andover House, Inc.. All rights reserved.

ACE-2, TMPRSS2, and Neuropilin-1 Receptor Expression on Human Brain Astrocytes and Pericytes and SARS-CoV-2 Infection Kinetics.

Angiotensin Converting Enzyme 2 (ACE-2), Transmembrane Serine Protease 2 (TMPRSS-2) and Neuropilin-1 cellular receptors support the entry of SARS-CoV-2 into susceptible human target cells and are characterized at the molecular level. Some evidence on the expression of entry receptors at mRNA and protein levels in brain cells is available, but co-expression of these receptors and confirmatory evidence on brain cells is lacking. SARS-CoV-2 infects some brain cell types, but infection susceptibility, multiple entry receptor density, and infection kinetics are rarely reported in specific brain cell types. Highly sensitive Taqman ddPCR, flow-cytometry and immunocytochemistry assays were used to quantitate the expression of ACE-2, TMPRSS-2 and Neuropilin-1 at mRNA and protein levels on human brain-extracted pericytes and astrocytes, which are an integral part of the Blood-Brain-Barrier (BBB). Astrocytes showed moderate ACE-2 (15.9 ± 1.3%, Mean ± SD, n = 2) and TMPRSS-2 (17.6%) positive cells, and in contrast show high Neuropilin-1 (56.4 ± 39.8%, n = 4) protein expression. Whereas pericytes showed variable ACE-2 (23.1 ± 20.7%, n = 2), Neuropilin-1 (30.3 ± 7.5%, n = 4) protein expression and higher TMPRSS-2 mRNA (667.2 ± 232.3, n = 3) expression. Co-expression of multiple entry receptors on astrocytes and pericytes allows entry of SARS-CoV-2 and progression of infection. Astrocytes showed roughly four-fold more virus in culture supernatants than pericytes. SARS-CoV-2 cellular entry receptor expression and "in vitro" viral kinetics in astrocytes and pericytes may improve our understanding of viral infection "in vivo". In addition, this study may facilitate the development of novel strategies to counter the effects of SARS-CoV-2 and inhibit viral infection in brain tissues to prevent the spread and interference in neuronal functions.

Neuropathogenesis and Neurological Manifestations of SARS-CoV-2

Neurological complications of COVID-19 contribute significantly to mortality in the intensive care unit (ICU). Preventive therapy, though discussed in literature, is limited for COVID-19 neurological manifestations and treatment algorithms continue to rely on evidence from previous pandemics. Thus, in this chapter we evaluate current in vitro, in vitro, histopathological studies to ascertain the most likely mechanisms of SARS-CoV-2 central nervous system entry. From this understanding, we determine probable mechanisms for neurological compilations observed in COVID-19 as relevant to the clinician. SARS-CoV-2 infection of nasal epithelium and the respiratory tract may allow for a systemic inflammatory response that results in neuroinflammation. While most neurological complications are inflammatory in etiology, rarely, SARS-CoV-2 may enter into the central nervous system and mediate neuronal damage. © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2022.

A year in review: brain barriers and brain fluids research in 2022.

This aim of this editorial is to highlight progress made in brain barrier and brain fluid research in 2022. It covers studies on the blood-brain, blood-retina and blood-CSF barriers (choroid plexus and meninges), signaling within the neurovascular unit and elements of the brain fluid systems. It further discusses how brain barriers and brain fluid systems are impacted in CNS diseases, their role in disease progression and progress being made in treating such diseases.

Csf & Plasma Soluble Biomarkers in Neuro-Pasc: Preliminary Results from Covid Mind

Background: It is unknown whether individuals with neurological post-acute sequelae of COVID-19 (NeuroPASC) display altered levels of neuroimmune activity or neuronal injury. Method(s): Participants with new or worsened neurologic symptoms at least 3 months after laboratory-confirmed COVID-19 were enrolled in The COVID Mind Study at Yale. Never COVID controls (no history of COVID-19;nucleocapsid (N) antibody negative) were pre-pandemic or prospectively enrolled volunteers. CSF and plasma were assessed for neopterin and for IL-1beta, IL-1RA, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p40, IL-12p70, IL-13, MCP-1, TNFalpha by bead-based multiplex assay;and for anti-SARS-CoV-2 N antibodies by Luminex-based multiplex assay in technical replicate, normalized against bovine serum albumin conjugated beads. Plasma concentrations of D-dimer, C-reactive protein, neurofilament light chain (NFL), and glial fibrillary acid protein (GFAP) were measured using high-sensitivity immunoassays. Group comparisons used non-parametric tests. Result(s): NeuroPASC participants (n=38) were studied 329 (median) days (range 81-742) after first positive test for acute COVID-19. Cognitive impairment (84%) and fatigue (82%) were the most frequent post-COVID symptoms. NeuroPASC and controls (n=22) were median 49 vs 52 yrs old (p=0.9), 74% vs 32% female (p< 0.001), 76% vs 23% white race (p< 0.001), and 6% vs 57% smokers (p< 0.001). CSF white blood cells/mL, CSF protein, and serum:CSF albumin ratio were normal in both groups. CSF TNFalpha (0.66 vs 0.55 pg/ul) and plasma IL12p40 were higher (103.3 vs 42.7);and MCP-1 (503 vs 697 pg/ul) and IL-6 (1.32 vs 1.84 pg/ul;p < 0.05 for IL-6) were lower in NeuroPASC vs controls (p< 0.05);but none of these differences were significant after adjusting for multiple comparisons. Plasma GFAP was elevated in NeuroPASC vs controls (54.4 vs 42.3 pg/ml;adjusted p< 0.03). There were no differences in the other biomarkers tested. 10/31 and 7/31 NeuroPASC had anti-N antibodies in CSF and plasma, respectively. Conclusion(s): When comparing NeuroPASC to never COVID controls, we found no evidence of neuroinflammation (normal CSF cell count, inflammatory cytokines) or blood-brain barrier dysfunction (normal albumin ratio), and no support for ongoing neuronal damage (normal plasma NFL). Future studies should include better gender and race matched controls and should explore the significance of a persistent CNS humoral immune response to SARS-CoV-2 and elevated plasma GFAP after COVID-19. (Figure Presented).

Post-Covid Cognitive Impairment Mri Brain Scan Abnormalities: A Potential Biomarker

Background: Post-acute sequelae of SARS-COV-2 infection (PASC) is associated with cognitive impairment (CI) with unclear pathogenesis though blood brain barrier (BBB) impairment and excitotoxic injury appear significant. Post-acute sequelae of SARS-COV-2 infection (PASC) is associated with cognitive impairment (CI) with unclear pathogenesis though blood brain barrier (BBB) impairment and excitotoxic injury appear significant. We hypothesized that PASC CI patients would have brain inflammation and BBB disruption using advanced MR imaging. Method(s): In this prospective longitudinal study, 14 patients with PASC CI (mild and non-hospitalised) were enrolled (mean age of 45;10 F and 4 M) and 10 sex and age matched healthy controls. 13 had a follow up MR at 9-12 months (mean 10 months). All participants underwent DCE perfusion (an index of BBB integrity with Ktrans as the measurement), Diffusion Tensor Imaging (DTI) and single voxel MR spectroscopy (MRS) of the frontal cortex/white matter and the brainstem in addition to brain anatomical MRI. Between group analyses were used to determine which MRI outcomes were significantly different from controls in patients with PASC CI. Result(s): The PASCI CI group showed significantly increased (ie BBB impairment) Ktrans, and increased region (Frontal white matter and Brain Stem)-specific areas in the brain (p=< 0.005), reduction in NAA (ie neuronal injury) and mild reduction of Glx (ie excitotoxicity) in the frontal white matter and brain stem (p=0.004), and reduction in white matter integrity (increased diffusivity -greater radial and mean diffusivity). Increased Ktrans was correlated with increased both radial and mean diffusivity (r=0.9) in all tested brain regions. Ktrans significantly improved in the follow up MR (p= 002596 Z=-2.794872) with no difference between subjects and controls indicating BBB normalisation (p= 0.442418, z= -0.144841). White matter integrity also improved especially in the fractional anisotropy values in the executive networks (p=< 0.00045). MRS showed significant improvement in the NAA in the frontal white matter but Glx remain high as compared to the controls (p=0.0006). Conclusion(s): PASC CI was characterised by reversible diffuse BBB impairment, neuronal/axonal and excitotoxic injury. BBB impairment was associated with white matter disruption. These are suggestive biomarkers for the presence, severity and prognosis of PASC CI. Such biomarkers could underpin appropriate trial design and timing of intervention.

Inflammatory and Blood-Brain Barrier Markers after Covid-19 among People with Hiv

Background: COVID-19, the disease caused by SARS-CoV-2, has resulted in devastating morbidity and mortality worldwide. Alarming evidence indicates that long-term adverse outcomes of COVID-19 can affect all major systems of the body, including the immune, respiratory, cardiovascular, and neurological systems. While acute COVID-19 pathology does not appear to be markedly different by HIV status, long-term outcomes of COVID-19 in People with HIV (PWH) are unknown and require further investigation. This study evaluates the inflammatory profile longitudinally up to three months after COVID-19. In addition, markers of the blood-brain barrier (BBB) integrity and vascular dysfunction were also evaluated. Method(s): Plasma samples were collected from 15 males and 6 females with COVID-19 and HIV infection (COVID+/HIV+) and 9 males and 14 females with COVID-19 without HIV infection (COVID+/HIV-) between March 2020 and March 2021. Baseline samples were obtained approx. 10 days after COVID-19 diagnosis (T=0) and three months after (T=3). Mean age group for COVID+/HIV-was 45.4+/-17.8 years for males and 39.7+/-15.3 for females and for COVID+/HIV+ was 52.1+/-12.3 for males and 48.7+/-1 for females (N=15 and 6, respectively). 27 inflammatory molecules were measured by Bio-Plex Multiplex Immunoassay (Bio-Rad) and two markers of BBB and vascular dysfunction (soluble ICAM1 and S100beta) by ELISA. Result(s): Out of 27 inflammatory analytes, 20 had detectable signals. Eotaxin (CCL11) and G-CSF levels were differentially upregulated in the COVID+/HIV+ group as compared to the COVID+/HIV-group in both time point studied (Table 1). IFN-g showed sustained increased levels at T=3 in the COVID+/HIV+ group, whereas there was a significant reduction over time in the COVID+/HIV-group. At T3, inflammatory markers (IL-4, IL-8, IL-13, basic FGF, TNF-alpha, MIP-1alpha, and CCL2) either decreased or remained unchanged in both groups. In contrast, the markers of the BBB disruption and vascular dysfunction, such as S100beta and soluble ICAM-1 increased in the COVID+/HIV+ group, suggesting long-term progressive BBB and vascular alterations. Conclusion(s): HIV-1 may potentiate long COVID-19-induced neuropathology, with progressive BBB breakdown and sustained increase in eotaxin-1 and G-CSF. Plasma inflammatory markers in COVID-19 patients with or without HIV-1 co-infection.

Nanomedicines for brain diseases: where we are and where we are going.

Graphical abstract [Formula: see text].

Controversies around COVID-19 Vaccines and Antidepressants: Scope and Perspective in Malaysia.

BACKGROUND: Individuals with severe mental illness are prone to severe COVID-19 infection with increased morbidity and mortality. Psychiatric patients are often concerned about the potential interactions between the newly approved COVID-19 vaccines in Malaysia and psychotropic drugs like antidepressants. To date, such data are unavailable. OBJECTIVES: This review aims to clear the polemics of COVID-19 vaccine-antidepressants interaction in these 3 aspects: (1) cytokines and cytochrome P450 pathway, (2) blood-brain barrier (BBB) involvement and (3) and its interaction with polyethylene glycol (PEG), the potential allergenic culprit following COVID-19 vaccination. METHODS: A systemic scoping approach was employed to search for peer-reviewed journal articles across four healthcare and scientific databases (PubMed, MEDLINE, PsycINFO and Cumulative Index to Nursing and Allied Health Literature (CINAHL)). RESULTS: Antidepressants metabolism often involve the CYP450 enzymes. Vaccine-antidepressants interactions are probable, likely to be triggered by interactions of CYP450 enzymes and inflammatory cytokines, resulting in diminished drug metabolism and chemical detoxification. Aside, PEG, the excipient in mRNA-based COVID-19 vaccines and antidepressants, has been reported as the anaphylaxis causative allergen. However, whether it leads to a synergistic, potentiation or antagonistic effects when used in combination, remains to be elucidated. CONCLUSION: Psychotropic medications, including antidepressants, showed potentially relevant safety risk for COVID-19 patients. These vulnerable patient group must be prioritized for early access to safe and efficacious COVID-19 vaccines, as vaccination remains the most important public health intervention to tackle the ongoing COVID-19 pandemic.

Lipid nanoparticle-mediated drug delivery to the brain.

Lipid nanoparticles (LNPs) have revolutionized the field of drug delivery through their applications in siRNA delivery to the liver (Onpattro) and their use in the Pfizer-BioNTech and Moderna COVID-19 mRNA vaccines. While LNPs have been extensively studied for the delivery of RNA drugs to muscle and liver targets, their potential to deliver drugs to challenging tissue targets such as the brain remains underexplored. Multiple brain disorders currently lack safe and effective therapies and therefore repurposing LNPs could potentially be a game changer for improving drug delivery to cellular targets both at and across the blood-brain barrier (BBB). In this review, we will discuss (1) the rationale and factors involved in optimizing LNPs for brain delivery, (2) ionic liquid-coated LNPs as a potential approach for increasing LNP accumulation in the brain tissue and (3) considerations, open questions and potential opportunities in the development of LNPs for delivery to the brain.

Cerebellar syndrome as a complication of COVID-19 disease

COVID-19 disease is caused by the new coronavirus SARS-CoV-2. The disease first appeared in China in 2019 and quickly spread throughout the world. It primarily affects the respiratory tract, manifested by fever, cough and the devel-opment of dyspnoea, but the symptoms and complications can affect any organ system. Neurological symptoms include headaches, muscle and joint pain, taste and smell disorders. Complications include inflammatory diseases of the central nervous system, ataxia, peripheral nerve and muscle diseases, worsening of extra-pyramidal diseases, and neuropsychiatric disorders. This paper presents a case report of a 62-year-old man with cere bellar syndrome, ataxia, intentional tremor and hypermetria when dealing with COVID-19 disease.Copyright © 2021 Neuroendocrinology Letters.

A new kid in the folding funnel: Molecular chaperone activities of the BRICHOS domain.

The BRICHOS protein superfamily is a diverse group of proteins associated with a wide variety of human diseases, including respiratory distress, COVID-19, dementia, and cancer. A key characteristic of these proteins-besides their BRICHOS domain present in the ER lumen/extracellular part-is that they harbor an aggregation-prone region, which the BRICHOS domain is proposed to chaperone during biosynthesis. All so far studied BRICHOS domains modulate the aggregation pathway of various amyloid-forming substrates, but not all of them can keep denaturing proteins in a folding-competent state, in a similar manner as small heat shock proteins. Current evidence suggests that the ability to interfere with the aggregation pathways of substrates with entirely different end-point structures is dictated by BRICHOS quaternary structure as well as specific surface motifs. This review aims to provide an overview of the BRICHOS protein family and a perspective of the diverse molecular chaperone-like functions of various BRICHOS domains in relation to their structure and conformational plasticity. Furthermore, we speculate about the physiological implication of the diverse molecular chaperone functions and discuss the possibility to use the BRICHOS domain as a blood-brain barrier permeable molecular chaperone treatment of protein aggregation disorders.

Could SARS-CoV-2 Infection Be a Novel Risk Factor for Multiple Sclerosis?

The outbreak of the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has challenged the healthcare community worldwide. The SARS-CoV-2 primarily affects the respiratory system; however, strong evidence suggests that SARS-CoV-2 can be neuroinvasive, resulting in several neurological complications. It was previously assumed that some coronaviruses are involved in multiple sclerosis (MS) pathology via various mechanisms. The mechanisms involved in coronavirus-induced central demyelination are complex and largely redundant. Molecular mimicry was proposed to be one of the possible mechanisms. Disruption of the blood-brain barrier, dysregulation in several inflammatory cytokines, and upregulation of matrix metalloproteinases were also thought to induce central demyelinating pathology. This raises a question about the possible role of SARS-CoV-2 as a novel risk factor for MS.

Therapeutic role of columbianadin in human disorders: Medicinal importance, biological properties and analytical aspects

Introduction: Herbal medicines have been used for the treatment of human disorders and associated secondary complications since a very early age. Herbal medicines are composed with a variety of medicinal plants and their derived products. Coumarin class phytochemicals have an important role in medicine due to its anti-coagulant, anti-cancer, anti-HIV and anti-inflammatory activity. Herbal medicines have been gaining popularity in the modern system of medicine mainly due to its safety and efficacy. Columbianadin is an active phytochemical of Angelica pubescens and Heracleum candolleanum. Columbianadin have analgesic, anti-inflammatory, calcium-channel blocking properties and platelet aggregation inhibitory potential. Method(s): Present work described the medicinal importance and pharmacological activities of columbianadin in medicine supported by their traditional medicinal application and pharmacological activities. Scientific data of columbianadin has been collected from PubMed, Google Scholar, Google, Scopus, and Science Direct. However, scientific data of columbianadin published in Journals, books and scientific report have also been collected in the present paper. Analytical data of columbianadin have also been described to know the significance of analytical techniques for the isolation, and identification of columbianadin. Result(s): Scientific data of columbianadin signified the biological importance and therapeutic potential of columbianadin in medicine. Scientific data of columbianadin revealed their biological potential against inflammation, neuropathic pain, cancer, hepatic complications, and immune system disorders. However, biological effectiveness of columbianadin on blood-brain barrier permeability, body tissue, channels and platelet has also been discussed in the present work. Moreover, its therapeutic effectiveness against nematodes has been also summarized in this work. Analytical data for the isolation and identification of columbianadin in different samples has also been presented in this work. Discussion(s): Present work signified the biological importance and therapeutic potential of columbianadin in medicine, which could be used for the treatment of human disorders and associated secondary complications.Copyright © 2022 The Author(s)

Neurological manifestations associated with SARS-CoV-2 infection: an updated review

SARS-CoV-2 is a single-stranded RNA virus that belongs to the group of seven coronaviruses that affect humans, and its infection causes the COVID-19 disease. The association between the COVID-19 condition and risk factors of neurological manifestations is unclear to date. This review aims to update the main neurological manifestations associated with SARS-CoV-2 disease. First, we present the hypothesis of the neuroinvasion mechanisms of SARS-CoV-2. Then, we discuss the possible symptoms related to patients with COVID-19 infection in the central and peripheral nervous systems, followed by the perspectives of diagnosis and treatment of possible neurological manifesta-tions. The hypothesis of the neuroinvasion mechanism includes direct routes, as the virus crosses the blood-brain barrier or the ACE2 receptor pathway role, and indirect pathways, such as malfunctions of the immune system and vascular system dysregulation. Various studies report COVID-19 consequences, such as neuroanatomic alterations and cognitive impairment, besides peripheral condi-tions, such as anosmia, ageusia, and Guillain Barre Syndrome. However, the het-erogeneity of the studies about neurologic damage in patients after COVID-19 infection precludes any generalization of current findings. Finally, new studies are necessary to understand the adequate diagnosis, therapeutic method of early treatment, and risk group of patients for neurological manifestations of COVID-19 post-infection.Copyright © 2023, Instituto de Investigaciones Clinicas. All rights reserved.

In Silico Insight into the Inhibitory Effects of Active Antidiabetic Compounds from Medicinal Plants Against SARS-CoV-2 Replication and Post-translational Modification

Background: The recent reemergence of the coronavirus (COVID-19) caused by the virus severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has prompted the search for effective treatments in the forms of drugs and vaccines. Aim(s): In this regard, we performed an in silico study on 39 active antidiabetic compounds of medicinal plants to provide insight into their possible inhibitory potentials against SARS-CoV-2 replications and post-translational modifications. Top 12 active antidiabetic compounds with potential for dual inhibition of the replications and post-translational modifications of SARS-CoV-2 were ana-lyzed. Result(s): Boswellic acids, celastrol, rutin, sanguinarine, silymarin, and withanolides expressed binding energy for 3-chymotrypsin-like protease (3CLpro) (-8.0 to-8.9 Kcal/mol), papain-like protease (PLpro) (-9.1 to-10.2 Kcal/mol), and RNA-dependent RNA polymerase (RdRp) (-8.5 to-9.1 Kcal/-mol) which were higher than the reference drugs (Lopinavir and Remdesivir) used in this study. Sanguinarine, silymarin, and withanolides are the most druggable phytochemicals among other phy-tochemicals as they follow Lipinski's rule of five analyses. Sanguinarine, silymarin, and withano-lides expressed moderate solubility with no hepatotoxicity, while silymarin and withanolides could not permeate the blood-brain barrier and showed no Salmonella typhimurium reverse mutation as-say (AMES) toxicity, unlike sanguinarine from the predictive absorption, distribution, metabolism, elimination, and toxicity (ADMET) studies. Conclusion(s): Sanguinarine, silymarin, and withanolides could be proposed for further experimental studies for their development as possible phytotherapy for the COVID-19 pandemic.Copyright © 2022 Bentham Science Publishers.