Efficacious Preclinical Repurposing of the Nucleoside Analogue Didanosine against COVID-19 Polymerase and Exonuclease

ACS Omega, Journal Year: 2022, Volume and Issue: 7(25), P. 21385 - 21396

Published: June 13, 2022

Analogues and derivatives of natural nucleosides/nucleotides are considered among the most successful bioactive species drug-like compounds in modern medicinal chemistry, as they well recognized for their diverse efficient pharmacological activities humans, especially antivirals antitumors. Coronavirus disease 2019 (COVID-19) is still almost incurable, with its infectious viral microbe, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continuing to wreak devastation around world. This global crisis pushed all involved scientists, including drug discoverers clinical researchers, try find an effective broad-spectrum anti-COVID-19 drug. Didanosine (2',3'-dideoxyinosine, DDI) a synthetic inosine/adenosine/guanosine analogue highly active antiretroviral therapeutic agent used treatment human immunodeficiency virus infection acquired (HIV/AIDS). potent reverse-transcriptase inhibitor characterized by proven strong effects against genome, which may successfully take part SARS-CoV-2/COVID-19. Additionally, targeting pivotal SARS-CoV-2 replication enzyme, RNA-dependent RNA polymerase (RdRp), very tactic combat COVID-19 irrespective variant type because RdRps broadly conserved strains. Herein, current study proved first time, using vitro antiviral evaluation, that DDI capable potently inhibiting novel virulent progenies quite tiny anti-SARS-CoV-2 anti-RdRp EC50 values 3.1 0.19 μM, respectively, surpassing remdesivir together metabolite (GS-441524). Thereafter, silico computational interpretation biological results supported strongly targets key pocket RdRp main catalytic site. The ideal pharmacophoric characteristics ligand make it typical multiplication processes (including high-fidelity proofreading), elastic structure open many kinds derivatization. In brief, present further uphold propose repurposing potentials different types convincingly motivate us quickly launch extensive preclinical/clinical evaluations, hoping combine protocols soon.

Language: Английский

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Comparative Analysis of Virology and Pathogenesis of SARS-CoV-2 and HIV Infections: Implications for Public Health and Treatment Strategies

Infection and Drug Resistance, Journal Year: 2025, Volume and Issue: Volume 18, P. 269 - 283

Published: Jan. 1, 2025

Introduction: Coronavirus Disease 19 (COVID-19), caused by the Severe Acute Respiratory Syndrome 2 (SARS-CoV -2), and Human Immunodeficiency Virus (HIV) are significant 21st-century pandemics with distinct virological clinical characteristics.COVID-19 primarily presents as an acute respiratory illness, while HIV leads to chronic immune suppression.Understanding their differences can enhance public health strategies treatment approaches.Purpose: This narrative review compares virology, transmission, responses, outcomes of SARS-CoV-2 inform interventions.Methods: A was conducted, synthesizing data from peer-reviewed literature expert commentary 2010 2024.Databases such PubMed, Cochrane Library, Google Scholar were searched for relevant studies.Results: spreads through airborne droplets contaminated surfaces, transmits direct contact infected bodily fluids.The response involves both innate adaptive systems, potentially leading a cytokine storm in severe cases.In contrast, evades system integrating into host cells, resulting infection progressive deterioration.Treatment focuses on symptom management prevention, antiviral medications vaccines playing crucial roles.Conversely, relies antiretroviral therapy (ART) suppress viral replication maintain function. Conclusion:The highlights nature versus progression HIV.Tailored prevention essential effective disease management.Recommendations: Public should address unique transmission routes viruses.Further research vaccine development therapeutic interventions is critical improving management.

Language: Английский

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Convergent Evolution Dynamics of SARS-CoV-2 and HIV Surface Envelope Glycoproteins Driven by Host Cell Surface Receptors and Lipid Rafts: Lessons for the Future

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(3), P. 1923 - 1923

Published: Jan. 18, 2023

Although very different, in terms of their genomic organization, enzymatic proteins, and structural HIV SARS-CoV-2 have an extraordinary evolutionary potential common. Faced with various selection pressures that may be generated by treatments or immune responses, these RNA viruses demonstrate high adaptive capacities, which result the continuous emergence variants quasi-species. In this retrospective analysis viral ensuring adhesion to plasma membrane host cells, we highlight many common points suggest convergent mechanisms evolution. first recognize a lipid raft microdomain acts as landing strip for particles on cell surface. case mucosal are primary targets both viruses, microdomains enriched anionic glycolipids (gangliosides) forming global electronegative field. Both use rafts surf surface search protein receptor able trigger fusion process. This implies envelope proteins geometrically electrically compatible biomolecules they select invade cells. present study, identify electrostatic critical parameter controlling evolution dynamics HIV-1 discuss impact phenotypic properties viruses. The virological data accumulated since early 1980s should help us face future virus pandemics.

Language: Английский

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HIV, HSV, SARS-CoV-2 and Ebola Share Long-Term Neuropsychiatric Sequelae

Neuropsychiatric Disease and Treatment, Journal Year: 2022, Volume and Issue: Volume 18, P. 2229 - 2237

Published: Oct. 1, 2022

Abstract: Long COVID, in which disease-related symptoms persist for months after recovery, has led to a revival of the discussion whether neuropsychiatric long-term viral infections indeed result from virulent activity or are purely psychological phenomena. In this review, we demonstrate that, despite showing differences structure and targeting, many viruses have highly similar effects on host. Herein, compare severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), human immunodeficiency virus 1 (HIV-1), Ebola disease (EVD), herpes simplex (HSV-1). We provide evidence that mutual anxiety, depression post-traumatic stress among these likely primary activity, thus suggesting share neuroinvasive strategies common. Moreover, it appears secondary induced environmental can lead emergence psychopathologies increased susceptibility (re)infection infected individuals. hypothesize positive feedback loop virus-environment-reinforced systemic responses exists. It is surmised cycle stress-induced reactivation, may be detrimental individuals by maintaining reinforcing host's immunocompromised state chronic inflammation, immunological strain, maladaptive central-nervous-system activity. propose perturbed cognitive processing promote aversive learning, manifest as acute, illness. Keywords: HIV-1, SARS virus, latency, neuropsychiatry, interoception

Language: Английский

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Immune Responses to SARS-CoV-2 in Pregnancy: Implications for the Health of the Next Generation

The Journal of Immunology, Journal Year: 2022, Volume and Issue: 209(8), P. 1465 - 1473

Published: Oct. 15, 2022

Abstract Widespread SARS-CoV-2 infection among pregnant individuals has led to a generation of fetuses exposed in utero, but the long-term impact such exposure remains unknown. Although fetal is rare, children born mothers with may be at increased risk for adverse neurodevelopmental and cardiometabolic outcomes. Fetal programming effects are likely mediated least part by maternal immune activation. In this review, we discuss recent evidence regarding prenatal on maternal, placental, response, as well implications health offspring. Extrapolating from what known about activation other contexts (e.g., obesity, HIV, influenza), review potential morbidity Based available data suggesting risk, highlight importance establishing large cohorts monitor offspring SARS-CoV-2–positive sequelae.

Language: Английский

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Natural killer cells and their exosomes in viral infections and related therapeutic approaches: where are we?

Cell Communication and Signaling, Journal Year: 2023, Volume and Issue: 21(1)

Published: Sept. 25, 2023

Innate immunity is the first line of host immune system to fight against infections. Natural killer cells are innate lymphocytes responsible for fighting virus-infected and cancerous cells. They have various mechanisms suppress viral On other hand, viruses evolved utilize different ways evade NK cell-mediated responses. Viruses can balance response by regulating cytokine release pattern changing proportion activating inhibitory receptors on surface Exosomes a subtype extracellular vesicles that involved in intercellular communication. Most cell populations these nano-sized vesicles, it was shown produce identical outcomes originating from which they released. In recent years, role cell-derived exosomes diseases including infections has been highlighted, drawing attention utilizing therapeutic potential nanoparticles. this article, used important initially examined. Subsequently, controlling discussed. Finally, current position treatment their reviewed. Video Abstract.

Language: Английский

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Combination therapies for COVID‐19: An overview of the clinical trials landscape

British Journal of Clinical Pharmacology, Journal Year: 2021, Volume and Issue: 88(4), P. 1590 - 1597

Published: Sept. 24, 2021

The COVID‐19 pandemic has driven an unprecedented level of global activity in drug discovery and clinical development for effective therapeutics targeting the coronavirus disease. There are currently 744 being tested 2879 trials globally. Almost 90% these focused on monotherapies. Combination therapies mainstay antiviral to increase potency individual compounds combat rapid evolution resistance, although combination have inherently complex regulatory challenges. Increased understanding SARS‐CoV‐2 lifecycle pathology provides a scientific rationale evaluating effectiveness different combinations. In this paper, we provide overview current trial landscape through weekly scanning national international registries. Our analysis delves specifically into dual what can be defined as “pivotal trials” (active, randomised, controlled at least phase II), with focus new repurposed therapeutic candidates that shown positive signals and/or been granted authorisation emergency use based efficacy safety data.

Language: Английский

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The emerging role of perivascular cells (pericytes) in viral pathogenesis

Journal of General Virology, Journal Year: 2021, Volume and Issue: 102(8)

Published: Aug. 23, 2021

Viruses may exploit the cardiovascular system to facilitate transmission or within-host dissemination, and symptoms of many viral diseases stem at least in part from a loss vascular integrity. The microvascular architecture is comprised an endothelial cell barrier ensheathed by perivascular cells (pericytes). Pericytes are antigen-presenting (APCs) play crucial roles angiogenesis maintenance integrity through complex reciprocal contact-mediated paracrine crosstalk with cells. We here review emerging ways that viruses interact pericytes pay consideration how these interactions influence function pathogenesis. Major outcomes virus-pericyte include leakage haemorrhage, organ tropism facilitated disruption, including penetration blood-brain placenta, as well inflammatory, neurological, cognitive developmental sequelae. underlying pathogenic mechanisms direct infection pericytes, pericyte modulation secreted gene products and/or dysregulation signalling pericytes. we cover herpesvirus human cytomegalovirus (HCMV, Human betaherpesvirus 5 ), retrovirus immunodeficiency virus (HIV; causative agent acquired syndrome, AIDS, HIV-associated neurocognitive disorder, HAND), flaviviruses dengue (DENV), Japanese encephalitis (JEV) Zika (ZIKV), coronavirus severe acute respiratory syndrome-related 2 (SARS-CoV-2; disease 2019, COVID-19). touch on promising pericyte-focussed therapies for treating caused important pathogens, which causing new long-standing global pandemics.

Language: Английский

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Metabolomic Profiling Reveals Potential Biomarkers and Prominent Features in HIV/AIDS Patients Co-Infected with SARS-CoV-2

Microorganisms, Journal Year: 2025, Volume and Issue: 13(1), P. 144 - 144

Published: Jan. 13, 2025

The underlying mechanisms and diagnostic biomarkers for the progress of COVID-19 in HIV patients have not been fully elucidated. In this study, aim is to analyze metabolomic profiles HIV/AIDS co-infected with SARS-CoV-2 identify indicative co-infection. we conducted a retrospective cohort analysis peripheral blood samples collected from 30 (pc group) without (nc group). through non-targeted metabolomics lipidomics analysis, 77 differential metabolites were identified plasma compared nc group, vitamin K1 emerging as significant feature. Moreover, pc group showed disturbances lipid metabolism, elevated triglycerides (TG) phosphatidylcholine (PC) decreased phosphatidylglycerol (PG) control group. Vitamin may be biomarker patients, changes levels TG, PC, PG molecules appear main features following co-infection COVID-19. emphasis our study on power using comprehensive (lipidomics) approaches metabolic potential patients.

Language: Английский

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John Cunningham Virus and Progressive Multifocal Leukoencephalopathy: A Falsely Played Diagnosis

Diseases, Journal Year: 2024, Volume and Issue: 12(5), P. 100 - 100

Published: May 13, 2024

Progressive Multifocal Leukoencephalopathy (PML) is a possibly fatal demyelinating disease and John Cunningham Polyomavirus (JCPyV) believed to cause this condition. The so-called JCPyV was initially reported in lymphoma Human Immunodeficiency Virus (HIV) cases, whereas nowadays, its incidence increasing Multiple Sclerosis (MS) cases treated with natalizumab (Tysabri). However, there are conflicting literature data on pathology diagnosis, some misdiagnosed reports exist, giving rise further questions towards the topic. In reality, PML supposed not what they seem be. addition, novel more frequent PML-like conditions may be reported, especially after Coronavirus Disease 2019 (COVID-19) pandemic.

Language: Английский

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