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Molecular Interactions and Mechanisms of COVID-19 Inhibition 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (15 March 2023) | Viewed by 20238

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Prof. Dr. Francesco Caruso

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Department of Chemistry, Vassar College, Poughkeepsie, NY 12604, USA
Interests: antioxidants; natural products; docking; structure-activity relationship; antitumor metal compounds
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Prof. Dr. Miriam Rossi

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Department of Chemistry, Vassar College, Poughkeepsie, NY 12604, USA
Interests: natural products; single crystal X-ray diffraction structure elucidation; metal complexes of natural products; anti-tumor compounds
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Dear Colleagues,

The COVID-19 pandemic is taking a large toll on the health care systems of all countries. Although vaccines are now available, there are many questions that remain to be answered. For instance, how long will vaccine-acquired immunity last? How effective will the vaccines be for current Omicron variants, and, perhaps more importantly, for future variants? The scientific community is active in pursuing studies that are aimed at alleviating the suffering of COVID-19 patients. It is clear that better drugs are needed, and the medical community is disclosing encouraging results. However, as chemists, biologists, and virologists, we are also called to participate in solving this problem. This Special Issue of IJMS will contribute to our present knowledge of and will clarify the processes that can address potential solutions towards COVID-19. More specifically, we will focus on addressing the molecular mechanisms that can assist in finding useful treatments. Targets of COVID-19 include spike and ACE2 proteins and the main 3Cl protease, papain protease, RdRp, Helicase, Nsp13, TMPRSS-2, etc.

Prof. Dr. Francesco Caruso
Prof. Dr. Miriam Rossi
Guest Editors

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Keywords

SARS
COVID-19
main protease 3CLpro
papain protease PLpro
Spike
ACE2
RdRp
Cytokine
Helicase
Nsp13
TMPRSS-2

Published Papers (10 papers)

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Research

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12 pages, 1157 KiB

Open AccessArticle

The Impact of Serum Levels of Reactive Oxygen and Nitrogen Species on the Disease Severity of COVID-19

by Sameh A. Ahmed, Yaser M. Alahmadi and Yasser A. Abdou

Int. J. Mol. Sci. 2023, 24(10), 8973; https://doi.org/10.3390/ijms24108973 - 18 May 2023

Cited by 5 | Viewed by 1378

Abstract

Elucidation of the redox pathways in severe coronavirus disease 2019 (COVID-19) might aid in the treatment and management of the disease. However, the roles of individual reactive oxygen species (ROS) and individual reactive nitrogen species (RNS) in COVID-19 severity have not been studied to date. The main objective of this research was to assess the levels of individual ROS and RNS in the sera of COVID-19 patients. The roles of individual ROS and RNS in COVID-19 severity and their usefulness as potential disease severity biomarkers were also clarified for the first time. The current case-control study enrolled 110 COVID-19-positive patients and 50 healthy controls of both genders. The serum levels of three individual RNS (nitric oxide (NO^•), nitrogen dioxide (ONO⁻), and peroxynitrite (ONOO⁻)) and four ROS (superoxide anion (O₂^•−), hydroxyl radical (^•OH), singlet oxygen (¹O₂), and hydrogen peroxide (H₂O₂)) were measured. All subjects underwent thorough clinical and routine laboratory evaluations. The main biochemical markers for disease severity were measured and correlated with the ROS and RNS levels, and they included tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), the neutrophil-to-lymphocyte ratio (NLR), and angiotensin-converting enzyme 2 (ACE2). The results indicated that the serum levels of individual ROS and RNS were significantly higher in COVID-19 patients than in healthy subjects. The correlations between the serum levels of ROS and RNS and the biochemical markers ranged from moderate to very strongly positive. Moreover, significantly elevated serum levels of ROS and RNS were observed in intensive care unit (ICU) patients compared with non-ICU patients. Thus, ROS and RNS concentrations in serum can be used as biomarkers to track the prognosis of COVID-19. This investigation demonstrated that oxidative and nitrative stress play a role in the etiology of COVID-19 and contribute to disease severity; thus, ROS and RNS are probable innovative targets in COVID-19 therapeutics. Full article

(This article belongs to the Special Issue Molecular Interactions and Mechanisms of COVID-19 Inhibition 2.0)

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11 pages, 1960 KiB

Open AccessArticle

SARS-CoV-2 Binding and Neutralization Properties of Peptides Derived from N-Terminus of Human ACE2

by Irina V. Astrakhantseva, Alina E. Ershova, Sergei A. Chuvpilo, Natalia A. Kruglova, Aydar A. Ishmukhametov, Marina S. Drutskaya, Liubov I. Kozlovskaya and Sergei A. Nedospasov

Int. J. Mol. Sci. 2023, 24(9), 8269; https://doi.org/10.3390/ijms24098269 - 05 May 2023

Cited by 1 | Viewed by 1429

Abstract

The binding properties of synthetic and recombinant peptides derived from N-terminal part of ACE2, the main receptor for SARS-CoV-2, were evaluated. Additionally, the ability of these peptides to prevent virus entry in vitro was addressed using both pseudovirus particles decorated with the S protein, as well as through infection of Vero cells with live SARS-CoV-2 virus. Surprisingly, in spite of effective binding to S protein, all linear peptides of various lengths failed to neutralize the viral infection in vitro. However, the P1st peptide that was chemically “stapled” in order to stabilize its alpha-helical structure was able to interfere with virus entry into ACE2-expressing cells. Interestingly, this peptide also neutralized pseudovirus particles decorated with S protein derived from the Omicron BA.1 virus, in spite of variations in key amino acid residues contacting ACE2. Full article

(This article belongs to the Special Issue Molecular Interactions and Mechanisms of COVID-19 Inhibition 2.0)

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11 pages, 2520 KiB

Open AccessArticle

In Silico and In Vitro Inhibition of SARS-CoV-2 PL^pro with Gramicidin D

by Sara Protić, Nevena Kaličanin, Milan Sencanski, Olivera Prodanović, Jelena Milicevic, Vladimir Perovic, Slobodan Paessler, Radivoje Prodanović and Sanja Glisic

Int. J. Mol. Sci. 2023, 24(3), 1955; https://doi.org/10.3390/ijms24031955 - 19 Jan 2023

Cited by 2 | Viewed by 1674

Abstract

Finding an effective drug to prevent or treat COVID-19 is of utmost importance in tcurrent pandemic. Since developing a new treatment takes a significant amount of time, drug repurposing can be an effective option for achieving a rapid response. This study used a combined in silico virtual screening protocol for candidate SARS-CoV-2 PL^pro inhibitors. The Drugbank database was searched first, using the Informational Spectrum Method for Small Molecules, followed by molecular docking. Gramicidin D was selected as a peptide drug, showing the best in silico interaction profile with PL^pro. After the expression and purification of PL^pro, gramicidin D was screened for protease inhibition in vitro and was found to be active against PL^pro. The current study’s findings are significant because it is critical to identify COVID-19 therapies that are efficient, affordable, and have a favorable safety profile. Full article

(This article belongs to the Special Issue Molecular Interactions and Mechanisms of COVID-19 Inhibition 2.0)

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14 pages, 2472 KiB

Open AccessArticle

Schizophyllum commune Reduces Expression of the SARS-CoV-2 Receptors ACE2 and TMPRSS2

by Te-Kai Sun, Wen-Chin Huang, Yu-Wen Sun, Jeng-Shyan Deng, Liang-Hsuan Chien, Ya-Ni Chou, Wen-Ping Jiang, Jaung-Geng Lin and Guan-Jhong Huang

Int. J. Mol. Sci. 2022, 23(23), 14766; https://doi.org/10.3390/ijms232314766 - 25 Nov 2022

Cited by 2 | Viewed by 2121

Abstract

The current global pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) of COVID-19 has infected hundreds of millions of people, killed millions, and continues to pose a threat. It has become one of the largest epidemics in human history, causing enormous damage to people’s lives and economies in the whole world. However, there are still many uncertainties and continued attention to the impact of SARS-CoV-2 on human health. The entry of SARS-CoV-2 into host cells is facilitated by the binding of the spike protein on the virus surface to the cell surface receptor angiotensin-converting enzyme 2 (ACE2). Furthermore, transmembrane protease serine 2 (TMPRSS2) is a host surface protease that cleaves and proteolytically activates its S protein, which is necessary for viral infection. Thus, SARS-CoV-2 uses the ACE2 receptor for cell entry and initiates the S protein using the protease TMPRSS2. Schizophyllum commune (SC) is one of the most widely distributed fungi, often found on the rotten wood of trees that has been found to have various health benefits, including anticancer, antimicrobial activity, antiparasitic, and immunomodulatory function. In this article, SC significantly diminished the expression ACE2 and TMPRSS2 protein in vitro and in vivo without cell damage. In addition, adenosine from SC was also proven in this experiment to reduce the ACE2 and TMPRSS2 expression. Thus, our findings suggest that SC and adenosine exhibit potential for the repression of SARS-CoV-2 infection via the ACE2 and TMPRSS2 axis. Full article

(This article belongs to the Special Issue Molecular Interactions and Mechanisms of COVID-19 Inhibition 2.0)

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12 pages, 2673 KiB

Open AccessArticle

Computational Analysis of SAM Analogs as Methyltransferase Inhibitors of nsp16/nsp10 Complex from SARS-CoV-2

by Alessandra M. Balieiro, Eduarda L. S. Anunciação, Clauber H. S. Costa, Wesam S. Qayed and José Rogério A. Silva

Int. J. Mol. Sci. 2022, 23(22), 13972; https://doi.org/10.3390/ijms232213972 - 12 Nov 2022

Viewed by 1230

Abstract

Methyltransferases (MTases) enzymes, responsible for RNA capping into severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are emerging important targets for the design of new anti-SARS-CoV-2 agents. Here, analogs of S-adenosylmethionine (SAM), obtained from the bioisosteric substitution of the sulfonium and amino acid groups, were evaluated by rigorous computational modeling techniques such as molecular dynamics (MD) simulations followed by relative binding free analysis against nsp16/nsp10 complex from SARS-CoV-2. The most potent inhibitor (2a) shows the lowest binding free energy (–58.75 Kcal/mol) and more potency than Sinefungin (SFG) (–39.8 Kcal/mol), a pan-MTase inhibitor, which agrees with experimental observations. Besides, our results suggest that the total binding free energy of each evaluated SAM analog is driven by van der Waals interactions which can explain their poor cell permeability, as observed in experimental essays. Overall, we provide a structural and energetic analysis for the inhibition of the nsp16/nsp10 complex involving the evaluated SAM analogs as potential inhibitors. Full article

(This article belongs to the Special Issue Molecular Interactions and Mechanisms of COVID-19 Inhibition 2.0)

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18 pages, 4288 KiB

Open AccessArticle

Long Chain N3-PUFA Decreases ACE2 Protein Levels and Prevents SARS-CoV-2 Cell Entry

by Shiqi Huang, Carla G. Taylor and Peter Zahradka

Int. J. Mol. Sci. 2022, 23(22), 13825; https://doi.org/10.3390/ijms232213825 - 10 Nov 2022

Cited by 2 | Viewed by 2489

Abstract

Angiotensin-converting enzyme 2 (ACE2) is a target of interest for both COVID-19 and cardiovascular disease management. Even though lower ACE2 levels may be beneficial in SARS-CoV-2 infectivity, maintaining the ACE1/ACE2 balance is also crucial for cardiovascular health. So far, reports describing conditions capable of altering ACE2 protein levels, especially via dietary components, are limited. In this study, the effects of omega-3 polyunsaturated fatty acids (n3-PUFA) on the protein levels of ACE1 and ACE2 in rodent tissues, human endothelial and kidney cell lines, and human plasma were examined. The ability of n3-PUFA to affect the entry of the SARS-CoV-2 pseudovirus into cells was also tested. Docosahexaenoic acid (DHA), and in some cases eicosapentaenoic acid (EPA), but not α-linoleic acid (ALA), reduced both ACE1 and ACE2 (non-glycosylated p100 and glycosylated p130 forms) in the heart, aorta, and kidneys of obese rats, as well as in human EA.hy926 endothelial and HEK293 kidney cells. Dietary supplementation with either DHA or ALA had no effect on plasma soluble ACE2 levels in humans. However, treatment of HEK293 cells with 80 and 125 µM DHA for 16 h inhibited the entry of the SARS-CoV-2 pseudovirus. These results strongly suggest that DHA treatment may reduce the ability of SARS-CoV-2 to infect cells via a mechanism involving a decrease in the absolute level of ACE2 protein as well as its glycosylation. Our findings warrant further evaluation of long-chain n3-PUFA supplements as a novel option for restricting SARS-CoV-2 infectivity in the general population. Full article

(This article belongs to the Special Issue Molecular Interactions and Mechanisms of COVID-19 Inhibition 2.0)

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10 pages, 6562 KiB

Open AccessCommunication

The Receptor Binding Domain of SARS-CoV-2 Lambda Variant Has a Better Chance Than the Delta Variant in Evading BNT162b2 COVID-19 mRNA Vaccine-Induced Humoral Immunity

by Haolin Liu, Pengcheng Wei, Katja Aviszus, Qianqian Zhang, Jared Linderberger, John Yang, Junfeng Liu, Zhongzhou Chen, Hassan Waheed, Lyndon Reynoso, Gregory P. Downey, Stephen K. Frankel, John W. Kappler, Philippa Marrack and Gongyi Zhang

Int. J. Mol. Sci. 2022, 23(19), 11325; https://doi.org/10.3390/ijms231911325 - 26 Sep 2022

Cited by 9 | Viewed by 1964

Abstract

The SARS-CoV-2 Delta and Lambda variants had been named variants of concern (VOC) and variants of interest (VOI), respectively, by the World Health Organization (WHO). Both variants have two mutations in the spike receptor binding domain (RBD) region, with L452R and T478K mutations in the Delta variant, and L452Q and F490S mutations in the Lambda variant. We used surface plasmon resonance (SPR)-based technology to evaluate the effect of these mutations on human angiotensin-converting enzyme 2 (ACE2) and Bamlanivimab binding. The affinity for the RBD ligand, ACE2, of the Delta RBD is approximately twice as strong as that of the wild type RBD, an increase that accounts for the increased infectivity of the Delta variant. On the other hand, in spite of its amino acid changes, the Lambda RBD has similar affinity to ACE2 as the wild type RBD. The protective anti-wild type RBD antibody Bamlanivimab binds very poorly to the Delta RBD and not at all to the Lambda RBD. Nevertheless, serum antibodies from individuals immunized with the BNT162b2 vaccine were found to bind well to the Delta RBD, but less efficiently to the Lambda RBD in contrast. As a result, the blocking ability of ACE2 binding by serum antibodies was decreased more by the Lambda than the Delta RBD. Titers of sera from BNT162b2 mRNA vaccinated individuals dropped 3-fold within six months of vaccination regardless of whether the target RBD was wild type, Delta or Lambda. This may account partially for the fall off with time in the protective effect of vaccines against any variant. Full article

(This article belongs to the Special Issue Molecular Interactions and Mechanisms of COVID-19 Inhibition 2.0)

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Review

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29 pages, 3210 KiB

Open AccessReview

SARS-CoV-2 Evasion of the Interferon System: Can We Restore Its Effectiveness?

by Alessandra Sacchi, Flavia Giannessi, Andrea Sabatini, Zulema Antonia Percario and Elisabetta Affabris

Int. J. Mol. Sci. 2023, 24(11), 9353; https://doi.org/10.3390/ijms24119353 - 27 May 2023

Cited by 3 | Viewed by 2536

Abstract

Type I and III Interferons (IFNs) are the first lines of defense in microbial infections. They critically block early animal virus infection, replication, spread, and tropism to promote the adaptive immune response. Type I IFNs induce a systemic response that impacts nearly every cell in the host, while type III IFNs’ susceptibility is restricted to anatomic barriers and selected immune cells. Both IFN types are critical cytokines for the antiviral response against epithelium-tropic viruses being effectors of innate immunity and regulators of the development of the adaptive immune response. Indeed, the innate antiviral immune response is essential to limit virus replication at the early stages of infection, thus reducing viral spread and pathogenesis. However, many animal viruses have evolved strategies to evade the antiviral immune response. The Coronaviridae are viruses with the largest genome among the RNA viruses. Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) caused the coronavirus disease 2019 (COVID-19) pandemic. The virus has evolved numerous strategies to contrast the IFN system immunity. We intend to describe the virus-mediated evasion of the IFN responses by going through the main phases: First, the molecular mechanisms involved; second, the role of the genetic background of IFN production during SARS-CoV-2 infection; and third, the potential novel approaches to contrast viral pathogenesis by restoring endogenous type I and III IFNs production and sensitivity at the sites of infection. Full article

(This article belongs to the Special Issue Molecular Interactions and Mechanisms of COVID-19 Inhibition 2.0)

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34 pages, 2800 KiB

Open AccessReview

Lessons Learnt from COVID-19: Computational Strategies for Facing Present and Future Pandemics

by Matteo Pavan and Stefano Moro

Int. J. Mol. Sci. 2023, 24(5), 4401; https://doi.org/10.3390/ijms24054401 - 23 Feb 2023

Cited by 3 | Viewed by 2534

Abstract

Since its outbreak in December 2019, the COVID-19 pandemic has caused the death of more than 6.5 million people around the world. The high transmissibility of its causative agent, the SARS-CoV-2 virus, coupled with its potentially lethal outcome, provoked a profound global economic and social crisis. The urgency of finding suitable pharmacological tools to tame the pandemic shed light on the ever-increasing importance of computer simulations in rationalizing and speeding up the design of new drugs, further stressing the need for developing quick and reliable methods to identify novel active molecules and characterize their mechanism of action. In the present work, we aim at providing the reader with a general overview of the COVID-19 pandemic, discussing the hallmarks in its management, from the initial attempts at drug repurposing to the commercialization of Paxlovid, the first orally available COVID-19 drug. Furthermore, we analyze and discuss the role of computer-aided drug discovery (CADD) techniques, especially those that fall in the structure-based drug design (SBDD) category, in facing present and future pandemics, by showcasing several successful examples of drug discovery campaigns where commonly used methods such as docking and molecular dynamics have been employed in the rational design of effective therapeutic entities against COVID-19. Full article

(This article belongs to the Special Issue Molecular Interactions and Mechanisms of COVID-19 Inhibition 2.0)

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10 pages, 278 KiB

Open AccessReview

Endogenous miRNA-Based Innate-Immunity against SARS-CoV-2 Invasion of the Brain

by Walter J. Lukiw and Aileen I. Pogue

Int. J. Mol. Sci. 2023, 24(4), 3363; https://doi.org/10.3390/ijms24043363 - 08 Feb 2023

Viewed by 1820

Abstract

The severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2), the causative agent of COVID-19, possesses an unusually large positive-sense, single-stranded viral RNA (ssvRNA) genome of about ~29,903 nucleotides (nt). In many respects, this ssvRNA resembles a very large, polycistronic messenger RNA (mRNA) possessing a 5′-methyl cap (m⁷GpppN), a 3′- and 5′-untranslated region (3′-UTR, 5′-UTR), and a poly-adenylated (poly-A+) tail. As such, the SARS-CoV-2 ssvRNA is susceptible to targeting by small non-coding RNA (sncRNA) and/or microRNA (miRNA), as well as neutralization and/or inhibition of its infectivity via the human body’s natural complement of about ~2650 miRNA species. Depending on host cell and tissue type, in silico analysis, RNA sequencing, and molecular-genetic investigations indicate that, remarkably, almost every single human miRNA has the potential to interact with the primary sequence of SARS-CoV-2 ssvRNA. Individual human variation in host miRNA abundance, speciation, and complexity among different human populations and additional variability in the cell and tissue distribution of the SARS-CoV-2 angiotensin converting enzyme-2 (ACE2) receptor (ACE2R) appear to further contribute to the molecular-genetic basis for the wide variation in individual host cell and tissue susceptibility to COVID-19 infection. In this paper, we review recently described aspects of the miRNA and ssvRNA ribonucleotide sequence structure in this highly evolved miRNA–ssvRNA recognition and signaling system and, for the first time, report the most abundant miRNAs in the control superior temporal lobe neocortex (STLN), an anatomical area involved in cognition and targeted by both SARS-CoV-2 invasion and Alzheimer’s disease (AD). We further evaluate important factors involving the neurotropic nature of SARS-CoV-2 and miRNAs and ACE2R distribution in the STLN that modulate significant functional deficits in the brain and CNS associated with SARS-CoV-2 infection and COVID-19’s long-term neurological effects. Full article

(This article belongs to the Special Issue Molecular Interactions and Mechanisms of COVID-19 Inhibition 2.0)

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