Man-Specific, GalNAc/T/Tn-Specific and Neu5Ac-Specific Seaweed Lectins as Glycan Probes for the SARS-CoV-2 (COVID-19) Coronavirus

Seaweed lectins, especially high-mannose-specific lectins from red algae, have been identified as potential antiviral agents that are capable of blocking the replication of various enveloped viruses like influenza virus, herpes virus, and HIV-1 in vitro. Their antiviral activity depends on the recognition of glycoprotein receptors on the surface of sensitive host cells—in particular, hemagglutinin for influenza virus or gp120 for HIV-1, which in turn triggers fusion events, allowing the entry of the viral genome into the cells and its subsequent replication. The diversity of glycans present on the S-glycoproteins forming the spikes covering the SARS-CoV-2 envelope, essentially complex type N-glycans and high-mannose type N-glycans, suggests that high-mannose-specific seaweed lectins are particularly well adapted as glycan probes for coronaviruses. This review presents a detailed study of the carbohydrate-binding specificity of high-mannose-specific seaweed lectins, demonstrating their potential to be used as specific glycan probes for coronaviruses, as well as the biomedical interest for both the detection and immobilization of SARS-CoV-2 to avoid shedding of the virus into the environment. The use of these seaweed lectins as replication blockers for SARS-CoV-2 is also discussed.

Download Full-text

High Mannose-binding Lectin with Preference for the Cluster of α1–2-Mannose from the Green Alga Boodlea coacta Is a Potent Entry Inhibitor of HIV-1 and Influenza Viruses

Journal of Biological Chemistry ◽

10.1074/jbc.m110.216655 ◽

2011 ◽

Vol 286 (22) ◽

pp. 19446-19458 ◽

Cited By ~ 42

Author(s):

Yuichiro Sato ◽

Makoto Hirayama ◽

Kinjiro Morimoto ◽

Naoki Yamamoto ◽

Satomi Okuyama ◽

...

Keyword(s):

Green Alga ◽

Influenza Viruses ◽

Viral Envelope ◽

Host Cells ◽

Carbohydrate Binding ◽

Sequence Motif ◽

High Association ◽

High Mannose ◽

Hiv 1 ◽

Boodlea Coacta

The complete amino acid sequence of a lectin from the green alga Boodlea coacta (BCA), which was determined by a combination of Edman degradation of its peptide fragments and cDNA cloning, revealed the following: 1) B. coacta used a noncanonical genetic code (where TAA and TAG codons encode glutamine rather than a translation termination), and 2) BCA consisted of three internal tandem-repeated domains, each of which contains the sequence motif similar to the carbohydrate-binding site of Galanthus nivalis agglutinin-related lectins. Carbohydrate binding specificity of BCA was examined by a centrifugal ultrafiltration-HPLC assay using 42 pyridylaminated oligosaccharides. BCA bound to high mannose-type N-glycans but not to the complex-type, hybrid-type core structure of N-glycans or oligosaccharides from glycolipids. This lectin had exclusive specificity for α1–2-linked mannose at the nonreducing terminus. The binding activity was enhanced as the number of terminal α1–2-linked mannose substitutions increased. Mannobiose, mannotriose, and mannopentaose were incapable of binding to BCA. Thus, BCA preferentially recognized the nonreducing terminal α1–2-mannose cluster as a primary target. As predicted from carbohydrate-binding propensity, this lectin inhibited the HIV-1 entry into the host cells at a half-maximal effective concentration of 8.2 nm. A high association constant (3.71 × 108m−1) of BCA with the HIV envelope glycoprotein gp120 was demonstrated by surface plasmon resonance analysis. Moreover, BCA showed the potent anti-influenza activity by directly binding to viral envelope hemagglutinin against various strains, including a clinical isolate of pandemic H1N1-2009 virus, revealing its potential as an antiviral reagent.

Download Full-text

Mannose-Specific Lectins from Marine Algae: Diverse Structural Scaffolds Associated to Common Virucidal and Anti-Cancer Properties

Marine Drugs ◽

10.3390/md17080440 ◽

2019 ◽

Vol 17 (8) ◽

pp. 440 ◽

Cited By ~ 5

Author(s):

Annick Barre ◽

Mathias Simplicien ◽

Hervé Benoist ◽

Els J.M. Van Damme ◽

Pierre Rougé

Keyword(s):

Diagnostic Tools ◽

Carbohydrate Binding ◽

Legume Lectin ◽

Therapeutic Drugs ◽

Anti Cancer ◽

Glycoprotein Gp120 ◽

Lectin Family ◽

High Mannose ◽

Hiv 1

To date, a number of mannose-specific lectins have been isolated and characterized from seaweeds, especially from red algae. In fact, man-specific seaweed lectins consist of different structural scaffolds harboring a single or a few carbohydrate-binding sites which specifically recognize mannose-containing glycans. Depending on the structural scaffold, man-specific seaweed lectins belong to five distinct structurally-related lectin families, namely (1) the griffithsin lectin family (β-prism I scaffold); (2) the Oscillatoria agardhii agglutinin homolog (OAAH) lectin family (β-barrel scaffold); (3) the legume lectin-like lectin family (β-sandwich scaffold); (4) the Galanthus nivalis agglutinin (GNA)-like lectin family (β-prism II scaffold); and, (5) the MFP2-like lectin family (MFP2-like scaffold). Another algal lectin from Ulva pertusa, has been inferred to the methanol dehydrogenase related lectin family, because it displays a rather different GlcNAc-specificity. In spite of these structural discrepancies, all members from the five lectin families share a common ability to specifically recognize man-containing glycans and, especially, high-mannose type glycans. Because of their mannose-binding specificity, these lectins have been used as valuable tools for deciphering and characterizing the complex mannose-containing glycans from the glycocalyx covering both normal and transformed cells, and as diagnostic tools and therapeutic drugs that specifically recognize the altered high-mannose N-glycans occurring at the surface of various cancer cells. In addition to these anti-cancer properties, man-specific seaweed lectins have been widely used as potent human immunodeficiency virus (HIV-1)-inactivating proteins, due to their capacity to specifically interact with the envelope glycoprotein gp120 and prevent the virion infectivity of HIV-1 towards the host CD4+ T-lymphocyte cells in vitro.

Download Full-text

Bromodomain and Extraterminal Protein Inhibitor, Apabetalone (RVX-208), Reduces ACE2 Expression and Attenuates SARS-Cov-2 Infection In Vitro

Biomedicines ◽

10.3390/biomedicines9040437 ◽

2021 ◽

Vol 9 (4) ◽

pp. 437

Author(s):

Dean Gilham ◽

Audrey L. Smith ◽

Li Fu ◽

Dalia Y. Moore ◽

Abenaya Muralidharan ◽

...

Keyword(s):

Antiviral Agents ◽

Host Cells ◽

Protein Inhibitor ◽

Angiotensin Converting Enzyme 2 ◽

Dipeptidyl Peptidase 4 ◽

Surface Receptors ◽

Bet Inhibitor ◽

Epigenetic Machinery ◽

Unexplored Area

Effective therapeutics are urgently needed to counter infection and improve outcomes for patients suffering from COVID-19 and to combat this pandemic. Manipulation of epigenetic machinery to influence viral infectivity of host cells is a relatively unexplored area. The bromodomain and extraterminal (BET) family of epigenetic readers have been reported to modulate SARS-CoV-2 infection. Herein, we demonstrate apabetalone, the most clinical advanced BET inhibitor, downregulates expression of cell surface receptors involved in SARS-CoV-2 entry, including angiotensin-converting enzyme 2 (ACE2) and dipeptidyl-peptidase 4 (DPP4 or CD26) in SARS-CoV-2 permissive cells. Moreover, we show that apabetalone inhibits SARS-CoV-2 infection in vitro to levels comparable to those of antiviral agents. Taken together, our study supports further evaluation of apabetalone to treat COVID-19, either alone or in combination with emerging therapeutics.

Download Full-text

Novel bis-Tetrahydrofuranylurethane-Containing Nonpeptidic Protease Inhibitor (PI) UIC-94017 (TMC114) with Potent Activity against Multi-PI-Resistant Human Immunodeficiency Virus In Vitro

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.47.10.3123-3129.2003 ◽

2003 ◽

Vol 47 (10) ◽

pp. 3123-3129 ◽

Cited By ~ 256

Author(s):

Yasuhiro Koh ◽

Hirotomo Nakata ◽

Kenji Maeda ◽

Hiromi Ogata ◽

Geoffrey Bilcer ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Protease Inhibitor ◽

Therapeutic Agent ◽

Close Contact ◽

Wide Spectrum ◽

Antiviral Agents ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT We designed, synthesized, and identified UIC-94017 (TMC114), a novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) containing a 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane (bis-THF) and a sulfonamide isostere which is extremely potent against laboratory HIV-1 strains and primary clinical isolates (50% inhibitory concentration [IC50], ∼0.003 μM; IC90, ∼0.009 μM) with minimal cytotoxicity (50% cytotoxic concentration for CD4+ MT-2 cells, 74 μM). UIC-94017 blocked the infectivity and replication of each of HIV-1NL4-3 variants exposed to and selected for resistance to saquinavir, indinavir, nelfinavir, or ritonavir at concentrations up to 5 μM (IC50s, 0.003 to 0.029 μM), although it was less active against HIV-1NL4-3 variants selected for resistance to amprenavir (IC50, 0.22 μM). UIC-94017 was also potent against multi-PI-resistant clinical HIV-1 variants isolated from patients who had no response to existing antiviral regimens after having received a variety of antiviral agents. Structural analyses revealed that the close contact of UIC-94017 with the main chains of the protease active-site amino acids (Asp-29 and Asp-30) is important for its potency and wide spectrum of activity against multi-PI-resistant HIV-1 variants. Considering the favorable pharmacokinetics of UIC-94017 when administered with ritonavir, the present data warrant that UIC-94017 be further developed as a potential therapeutic agent for the treatment of primary and multi-PI-resistant HIV-1 infections.

Download Full-text

Novel Intersubunit Interaction Critical for HIV-1 Core Assembly Defines a Potentially Targetable Inhibitor Binding Pocket

mBio ◽

10.1128/mbio.02858-18 ◽

2019 ◽

Vol 10 (2) ◽

Cited By ~ 6

Author(s):

Pierrick Craveur ◽

Anna T. Gres ◽

Karen A. Kirby ◽

Dandan Liu ◽

John A. Hammond ◽

...

Keyword(s):

Viral Replication ◽

Specific Interaction ◽

Binding Pocket ◽

Core Stability ◽

Host Cells ◽

Capsid Assembly ◽

Dynamic Simulations ◽

Virus Like Particle ◽

Hiv 1

ABSTRACTHIV-1 capsid protein (CA) plays critical roles in both early and late stages of the viral replication cycle. Mutagenesis and structural experiments have revealed that capsid core stability significantly affects uncoating and initiation of reverse transcription in host cells. This has led to efforts in developing antivirals targeting CA and its assembly, although none of the currently identified compounds are used in the clinic for treatment of HIV infection. A specific interaction that is primarily present in pentameric interfaces in the HIV-1 capsid core was identified and is reported to be important for CA assembly. This is shown by multidisciplinary characterization of CA site-directed mutants using biochemical analysis of virus-like particle formation, transmission electron microscopy ofin vitroassembly, crystallographic studies, and molecular dynamic simulations. The data are consistent with a model where a hydrogen bond between CA residues E28 and K30′ from neighboring N-terminal domains (CANTDs) is important for CA pentamer interactions during core assembly. This pentamer-preferred interaction forms part of anN-terminaldomaininterface (NDI) pocket that is amenable to antiviral targeting.IMPORTANCEPrecise assembly and disassembly of the HIV-1 capsid core are key to the success of viral replication. The forces that govern capsid core formation and dissociation involve intricate interactions between pentamers and hexamers formed by HIV-1 CA. We identified one particular interaction between E28 of one CA and K30′ of the adjacent CA that appears more frequently in pentamers than in hexamers and that is important for capsid assembly. Targeting the corresponding site could lead to the development of antivirals which disrupt this interaction and affect capsid assembly.

Download Full-text

Lentiviral Nef Proteins Utilize PAK2-Mediated Deregulation of Cofilin as a General Strategy To Interfere with Actin Remodeling

Journal of Virology ◽

10.1128/jvi.02467-09 ◽

2010 ◽

Vol 84 (8) ◽

pp. 3935-3948 ◽

Cited By ~ 43

Author(s):

Bettina Stolp ◽

Libin Abraham ◽

Jochen M. Rudolph ◽

Oliver T. Fackler

Keyword(s):

Host Cells ◽

General Strategy ◽

Actin Remodeling ◽

Mechanistic Analysis ◽

Immunodeficiency Virus ◽

Hiv Type 1 ◽

Hiv 1

ABSTRACT Nef is an accessory protein and pathogenicity factor of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) which elevates virus replication in vivo. We recently described for HIV type 1SF2 (HIV-1SF2) the potent interference of Nef with T-lymphocyte chemotaxis via its association with the cellular kinase PAK2. Mechanistic analysis revealed that this interaction results in deregulation of the actin-severing factor cofilin and thus blocks the chemokine-mediated actin remodeling required for cell motility. However, the efficiency of PAK2 association is highly variable among Nef proteins from different lentiviruses, prompting us to evaluate the conservation of this actin-remodeling/cofilin-deregulating mechanism. Based on the analysis of a total of 17 HIV-1, HIV-2, and SIV Nef proteins, we report here that inhibition of chemokine-induced actin remodeling as well as inactivation of cofilin are strongly conserved activities of lentiviral Nef proteins. Of note, even for Nef variants that display only marginal PAK2 association in vitro, these activities require the integrity of a PAK2 recruitment motif and the presence of endogenous PAK2. Thus, reduced in vitro affinity to PAK2 does not indicate limited functionality of Nef-PAK2 complexes in intact HIV-1 host cells. These results establish hijacking of PAK2 for deregulation of cofilin and inhibition of triggered actin remodeling as a highly conserved function of lentiviral Nef proteins, supporting the notion that PAK2 association may be critical for Nef's activity in vivo.

Download Full-text

In vitro Evaluation of the antiviral effects of acemannan on the replication and pathogenesis of HIV-1 and other enveloped viruses: Modification of the processing of glycoprotein precursors

Antiviral Research ◽

10.1016/0166-3542(90)90156-2 ◽

1990 ◽

Vol 13 ◽

pp. 83 ◽

Cited By ~ 7

Keyword(s):

In Vitro Evaluation ◽

Enveloped Viruses ◽

Antiviral Effects ◽

Hiv 1

Download Full-text

NICTABA and UDA, two GlcNAc-binding lectins with unique antiviral activity profiles

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkv034 ◽

2015 ◽

Vol 70 (6) ◽

pp. 1674-1685 ◽

Cited By ~ 7

Author(s):

Stephanie C. Gordts ◽

Marleen Renders ◽

Geoffrey Férir ◽

Dana Huskens ◽

Els J. M. Van Damme ◽

...

Keyword(s):

T Lymphocytes ◽

Antiviral Activity ◽

Influenza A ◽

Specific Binding ◽

Tobacco Plant ◽

Human Monoclonal Antibody ◽

Envelope Glycoproteins ◽

Carbohydrate Binding ◽

Enveloped Viruses ◽

Hiv 1

Abstract Objectives This study aimed to assess the antiviral properties of a unique lectin (NICTABA) produced by the tobacco plant, Nicotiana tabacum. Methods Cellular assays were used to investigate the antiviral activity of NICTABA and Urtica dioica agglutinin (UDA). Surface plasmon resonance (SPR) studies were performed to study the sugar specificity and the interactions of both lectins with the envelope glycoproteins of HIV-1. Results The N-acetyl-d-glucosamine (GlcNAc)-binding lectins exhibited broad-spectrum activity against several families of enveloped viruses including influenza A/B, Dengue virus type 2, herpes simplex virus types 1 and 2 and HIV-1/2. The IC50 of NICTABA for various HIV-1 strains, clinical isolates and HIV-2 assessed in PBMCs ranged from 5 to 30 nM. Furthermore, NICTABA inhibited syncytium formation between persistently HIV-1-infected T cells and uninfected CD4+ T lymphocytes and prevented DC-SIGN-mediated HIV-1 transmission to CD4+ target T lymphocytes. However, unlike many other antiviral carbohydrate-binding agents (CBAs) described so far, NICTABA did not block HIV-1 capture to DC-SIGN+ cells and it did not interfere with the binding of the human monoclonal antibody 2G12 to gp120. SPR studies with HIV-1 envelope glycoproteins showed that the affinity of NICTABA for gp120 and gp41 was in the low nanomolar range. The specific binding of NICTABA to gp120 could be prevented in the presence of a GlcNAc trimer, but not in the presence of mannose trimers. NICTABA displayed no antiviral activity against non-enveloped viruses. Conclusions Since CBAs possess a high genetic barrier for the development of viral resistance and NICTABA shows a broad antiviral activity profile, this CBA may qualify as a potential antiviral candidate with a pleiotropic mode of action aimed at targeting the entry of enveloped viruses.

Download Full-text