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Novel Approaches to Potential COVID-19 Molecular Therapeutics

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 20 April 2025 | Viewed by 9689

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Special Issue Editors

Dr. Monica Gelzo

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1. Department of Molecular Medicine and Medical Biotechnology, Federico II University of Naples, 80138 Naples, Italy
2. CEINGE-Biotecnologie Avanzate, Scarl, Via Gaetano Salvatore 486, 80145 Naples, Italy
Interests: COVID-19; cystic fibrosis; congenital defects of cholesterol metabolism; metabolomics; congenital diarrhea
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Dr. Felice Amato

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Dipartimento di Medicina Molecolare e Bioteconologie Mediche, Università di Napoli Federico II, 80131 Naples, Italy
Interests: COVID-19; cystic fibrosis; haemophilia; inherited peripheral thrombosis; congenital diarrhea
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Prof. Dr. Ivan Gentile

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Dipartimento di Medicina clinica e Chirurgia, Università degli Studi di Napoli Federico II, 80131 Naples, Italy
Interests: COVID-19; bacterial and fungal infections, antibiotics, HIV and AIDS, HCV, HBV
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Prof. Dr. Giuseppe Castaldo

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Department of Molecular Medicine and Medical Biotechnology, Università degli Studi di Napoli Federico II, 80131 Naples, Italy
Interests: COVID-19; cystic fibrosis; metabolomics; haemophilia; inherited peripheral thrombosis; congenital diarrhea
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Special Issue Information

Dear Colleagues,

At the start of the New Year 2020, SARS-CoV-2 appeared in the Chinese city of Wuhan and rapidly spread worldwide turning into a global pandemic. SARS-CoV-2 is similar to other zoonotic viruses such as the SARS-CoV responsible for Severe Acute Respiratory Syndrome (SARS) The diseases, named COVID-19, presents itself with mild to severe respiratory symptoms, sometimes leading to acute respiratory distress syndrome (ARDS), multiorgan failure (MOF) and death. The lethality of COVID-19, especially in unvaccinated and fragile patients, as well as the propensity of the virus to quickly spawn new variants, impose the design of new diagnostic tools for personalized diagnosis and treatment The scientists quickly focused their research on vaccines, antibodies, antivirals, and drugs for the management of the disease. In order to develop effective therapies, a number of strategies were envisaged, from drug repositioning to structure-based design of novel drugs. Furthermore, metabolomic studies have shed light on altered pathways in COVID-19, giving the cue to the design of new drugs or to specifically target altered pathways. In this special issue, we will collect manuscripts, research articles and review, describing the cutting edge of COVID-19 diagnostics and therapeutic approaches, including biomarkers-driven therapies.

Dr. Monica Gelzo
Dr. Felice Amato
Prof. Dr. Ivan Gentile
Prof. Dr. Giuseppe Castaldo
Guest Editors

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Keywords

COVID-19
vaccines
therapeutics
antivirals
monoclonal antibodies
personalized medicine

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Published Papers (5 papers)

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Research

12 pages, 2921 KiB

Open AccessArticle

Two-Stage Recognition Mechanism of the SARS-CoV-2 Receptor-Binding Domain to Angiotensin-Converting Enzyme-2 (ACE2)

by Iga Biskupek and Artur Gieldon

Int. J. Mol. Sci. 2024, 25(1), 679; https://doi.org/10.3390/ijms25010679 - 4 Jan 2024

Cited by 1 | Viewed by 1779

Abstract

The SARS-CoV-2 virus, commonly known as COVID-19, occurred in 2019. It is a highly contagious illness with effects ranging from mild symptoms to severe illness. It is also one of the best-known pathogens since more than 200,000 scientific papers occurred in the last few years. With the publication of the SARS-CoV-2 (SARS-CoV-2-CTD) spike (S) protein in a complex with human ACE2 (hACE2) (PDB (6LZG)), the molecular analysis of one of the most crucial steps on the infection pathway was possible. The aim of this manuscript is to simulate the most widely spread mutants of SARS-CoV-2, namely Alpha, Beta, Gamma, Delta, Omicron, and the first recognized variant (natural wild type). With the wide search of the hypersurface of the potential energy performed using the UNRES force field, the intermediate state of the ACE2–RBD complex was found. R403, K/N/T417, L455, F486, Y489, F495, Y501, and Y505 played a crucial role in the protein recognition mechanism. The intermediate state cannot be very stable since it will prevent the infection cascade. Full article

(This article belongs to the Special Issue Novel Approaches to Potential COVID-19 Molecular Therapeutics)

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16 pages, 2422 KiB

Open AccessArticle

VEGFR and DPP-IV as Markers of Severe COVID-19 and Predictors of ICU Admission

by Ewa Pius-Sadowska, Piotr Kulig, Anna Niedźwiedź, Bartłomiej Baumert, Karolina Łuczkowska, Dorota Rogińska, Anna Sobuś, Zofia Ulańczyk, Miłosz Kawa, Edyta Paczkowska, Miłosz Parczewski, Anna Machalińska and Bogusław Machaliński

Int. J. Mol. Sci. 2023, 24(23), 17003; https://doi.org/10.3390/ijms242317003 - 30 Nov 2023

Cited by 2 | Viewed by 1140

Abstract

The pathophysiology of the severe course of COVID-19 is multifactorial and not entirely elucidated. However, it is well known that the hyperinflammatory response and cytokine storm are paramount events leading to further complications. In this paper, we investigated the vascular response in the pathophysiology of severe COVID-19 and aimed to identify novel biomarkers predictive of ICU admission. The study group consisted of 210 patients diagnosed with COVID-19 (age range: 18–93; mean ± SD: 57.78 ± 14.16), while the control group consisted of 80 healthy individuals. We assessed the plasma concentrations of various vascular factors using the Luminex technique. Then, we isolated RNA from blood mononuclear cells and performed a bioinformatics analysis investigating various processes related to vascular response, inflammation and angiogenesis. Our results confirmed that severe COVID-19 is associated with vWF/ADAMTS 13 imbalance. High plasma concentrations of VEGFR and low DPP-IV may be potential predictors of ICU admission. SARS-CoV-2 infection impairs angiogenesis, hinders the generation of nitric oxide, and thus impedes vasodilation. The hypercoagulable state develops mainly in the early stages of the disease, which may contribute to the well-established complications of COVID-19. Full article

(This article belongs to the Special Issue Novel Approaches to Potential COVID-19 Molecular Therapeutics)

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19 pages, 1529 KiB

Open AccessArticle

Transcriptome from Paired Samples Improves the Power of Comprehensive COVID-19 Host-Viral Characterization

by Ognjen Milicevic, Ana Loncar, Dzihan Abazovic, Marija Vukcevic, Dragana Despot, Tatjana Djukic, Vladimir Djukic, Andjela Milovanovic, Nikola Panic, Nemanja Plecic and Ana Banko

Int. J. Mol. Sci. 2023, 24(17), 13125; https://doi.org/10.3390/ijms241713125 - 23 Aug 2023

Cited by 1 | Viewed by 1660

Abstract

Previous transcriptome profiling studies showed significantly upregulated genes and altered biological pathways in acute COVID-19. However, changes in the transcriptional signatures during a defined time frame are not yet examined and described. The aims of this study included viral metagenomics and evaluation of the total expression in time-matched and tissue-matched paired COVID-19 samples with the analysis of the host splicing profile to reveal potential therapeutic targets. Prospective analysis of paired nasopharyngeal swabs (NPS) and blood (BL) samples from 18 COVID-19 patients with acute and resolved infection performed using Kallisto, Suppa2, Centrifuge, EdgeR, PantherDB, and L1000CDS2 tools. In NPS, we discovered 6 genes with changed splicing and 40 differentially expressed genes (DEG) that yielded 88 altered pathways. Blood samples yielded 15 alternatively spliced genes. Although the unpaired DEG analysis failed, pairing identified 78 genes and 242 altered pathways with meaningful clinical interpretation and new candidate drug combinations with up to 65% overlap. Metagenomics analyses showed SARS-CoV-2 dominance during and after the acute infection, with a significant reduction in NPS (0.008 vs. 0.002, p = 0.019). Even though both NPS and BL give meaningful insights into expression changes, this is the first demonstration of how the power of blood analysis is vastly maximized by pairing. The obtained results essentially showed that pairing is a determinant between a failed and a comprehensive study. Finally, the bioinformatics results prove to be a comprehensive tool for full-action insights, drug development, and infectious disease research when designed properly. Full article

(This article belongs to the Special Issue Novel Approaches to Potential COVID-19 Molecular Therapeutics)

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16 pages, 1421 KiB

Open AccessArticle

Lipid Mediators and Cytokines/Chemokines Display Differential Profiles in Severe versus Mild/Moderate COVID-19 Patients

by Resmi Ravindran, Ellen O’Connor, Ajay Gupta, Paul A. Luciw, Aleena I. Khan, Nasrin Dorreh, Kate Chiang, Aamer Ikram and Srinivasa Reddy

Int. J. Mol. Sci. 2023, 24(17), 13054; https://doi.org/10.3390/ijms241713054 - 22 Aug 2023

Cited by 2 | Viewed by 1660

Abstract

Host immune responses play a key role in COVID-19 pathogenesis. The underlying phenomena are orchestrated by signaling molecules such as cytokines/chemokines and lipid mediators. These immune molecules, including anti-SARS-CoV-2 antibodies, interact with immune cells and regulate host responses, contributing to inflammation that drives the disease. We investigated 48 plasma cytokines/chemokines, 21 lipid mediators, and anti-S protein (RBD) antibodies in COVID-19 patients (n = 56) and non-COVID-19 respiratory disease controls (n = 49), to identify immune-biomarker profiles. Cytokines/chemokines (IL-6, CXCL-10 (IP-10), HGF, MIG, MCP-1, and G-CSF) and lipid mediators (TxB2, 11-HETE, 9-HODE, 13-HODE, 5-HETE, 12-HETE, 15-HETE, 14S-HDHA, 17S-HDHA, and 5-oxo ETE) were significantly elevated in COVID-19 patients compared to controls. In patients exhibiting severe disease, pro-inflammatory cytokines/chemokines (IL-6, CXCL-10, and HGF) and anti-SARS-CoV-2 antibodies were significantly elevated. In contrast, lipid mediators involved in the reduction/resolution of inflammation, in particular, 5-HETE, 11-HETE, and 5-oxoETE, were significantly elevated in mild/moderate disease. Taken together, these immune-biomarker profiles provide insight into immune responses related to COVID-19 pathogenesis. Importantly, our findings suggest that elevation in plasma concentrations of IL-6, CXCL-10, HGF, and anti-SARS-CoV-2 antibodies can predict severe disease, whereas elevation in lipid mediators peaks early (compared to cytokines) and includes induction of mechanisms leading to reduction of inflammation, associated complications, and maintenance of homeostasis. Full article

(This article belongs to the Special Issue Novel Approaches to Potential COVID-19 Molecular Therapeutics)

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17 pages, 25988 KiB

Open AccessArticle

Mycolactone: A Broad Spectrum Multitarget Antiviral Active in the Picomolar Range for COVID-19 Prevention and Cure

by Seth Osei Asiedu, Yash Gupta, Vlad Nicolaescu, Haley Gula, Thomas R. Caulfield, Ravi Durvasula, Prakasha Kempaiah, Samuel K. Kwofie and Michael D. Wilson

Int. J. Mol. Sci. 2023, 24(8), 7151; https://doi.org/10.3390/ijms24087151 - 12 Apr 2023

Viewed by 2534

Abstract

We have previously shown computationally that Mycolactone (MLN), a toxin produced by Mycobacterium ulcerans, strongly binds to Munc18b and other proteins, presumably blocking degranulation and exocytosis of blood platelets and mast cells. We investigated the effect of MLN on endocytosis using similar approaches, and it bound strongly to the N-terminal of the clathrin protein and a novel SARS-CoV-2 fusion protein. Experimentally, we found 100% inhibition up to 60 nM and 84% average inhibition at 30 nM in SARS-CoV-2 live viral assays. MLN was also 10× more potent than remdesivir and molnupiravir. MLN’s toxicity against human alveolar cell line A549, immortalized human fetal renal cell line HEK293, and human hepatoma cell line Huh7.1 were 17.12%, 40.30%, and 36.25%, respectively. The cytotoxicity IC₅₀ breakpoint ratio versus anti-SARS-CoV-2 activity was more than 65-fold. The IC₅₀ values against the alpha, delta, and Omicron variants were all below 0.020 µM, and 134.6 nM of MLN had 100% inhibition in an entry and spread assays. MLN is eclectic in its actions through its binding to Sec61, AT2R, and the novel fusion protein, making it a good drug candidate for treating and preventing COVID-19 and other similarly transmitted enveloped viruses and pathogens. Full article

(This article belongs to the Special Issue Novel Approaches to Potential COVID-19 Molecular Therapeutics)

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