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Sialic acid: an attractive biomarker with promising biomedical applications Cover

Sialic acid: an attractive biomarker with promising biomedical applications

Asian Biomedicine
Volume 16 (2022): Issue 4 (August 2022)
By: ,  ,  ,  ,   and    
Open Access
|Aug 2022
Figures & tables

Figures & Tables

Figure 1

(A) Chemical structure of the 3 main sialic acids, N-acetylneuraminic acid (Neu5Ac), N-glycolylneuraminic acid (Neu5Gc), and deaminoneuraminic acid (KDN). (B) Sialic acids are transferred onto acceptor glycans via sialyl transferase enzymes that use the activated cytidine-5′-monophosphate-sialic acid (CMP-Sia) as a donor molecule. Sialyl residues may be added terminally to galactose residues in α-2,3 or α-2,6 linkage, or to sialic acid residues in α-2,8 connection. Such glycan chains may be attached to glycoproteins via asparagine (N-glycan) or serine or threonine residues (O-glycans). Sialic acids may be released via hydrolytic enzymes called neuraminidases. (C) Examples of pathobiological interactions involving sialic acids with viruses, bacteria, hormones, and toxins. Gal, galactose; GalNAc, N-acetylgalactosamine; Man, mannose; Glc, glucose; GlcNAc, N-acetylglucosamine; Fuc, fucose.

Table 1

Viruses with specific binding to sialic acid derivatives

Virus nameViral genusViral familyGenome typeEnvelopeSialic acid receptorViral attachment proteinHost(s)Refs.
Influenza A virusAlphainfluenza-virusOrthomyxoviridaessRNAYesNeu5Acα2-3/6Gal, Neu5Acα23/6GalNAc, Neu5Acα2-6GlcNAcHA, NABirds and mammals[8, 13,14,15, 95]
Influenza B virusBetainfluenza-virusOrthomyxoviridaessRNAYesNeu5Acα2-3/6Gal, Neu5Acα23/6GalNAc, Neu5Acα2-6GlcNAcHA, NAHuman and seals[8, 13,14,15, 95]
Influenza C virusGammainfluenza-virusOrthomyxoviridaessRNAYesN-Acetyl-9-O-acetylneuraminic acid (Neu5,9Ac2)HEFHuman[95,96,97]
Salmon isavirusIsa-virusOrthomyxoviridaessRNAYes4-O-5-N-Acetylneuraminic acid (Neu4,5Ac2)HEFish[95, 98, 99]
TGEVAlphacorona-virusCoronaviridaessRNAYesα2-3-linked N-glycolylneuraminic acidHAPigs[6, 100, 101]
BCoV, HCoVOC43Betacorona-virusCoronaviridaessRNAYes9-O-Acetylated sialic acidHE, S proteinBovine and Human[6, 102]
SARS-CoV-2Betacorona-virusCoronaviridaessRNAYesN-Acetylneuraminic acidS proteinHuman[103]
IBVGammacorona-virusCoronaviridaessRNAYesα-2-3-Linked sialic acidHABirds[6, 104]
Bovine torovirusToro-virusCoronaviridaessRNAYesNeu5,9Ac2 and N-acetyl-7,9-O-acetylneuraminic acidHEBovine[6, 20]
HPIV1Respiro-virusParamyxoviridaessRNAYesα-2-3-Linked sialic acidHA, NAHuman[6]
Murine norovirusNoro-virusCaliciviridaessRNANoTerminal sialic acid in GD1aVP1Murine[105, 106]
Enterovirus 70Entero-virusPicornaviridaessRNANoO-Linked glycans containing sialic acid α2-3-linked to galactose(DAF/CD55)Human[107, 108]
Human rotavirusRota-virusReoviridaedsRNANoGM1VP4Human[6]
Murine polyomavirusAlphapolyoma-virusPolyomaviridaedsDNANoNeu5Acα2-3-GalVP1Murine[6]

[i] Neu5Ac, N-acetylneuraminic acid; Gal, galactose; GalNAc, N-acetyl galactose; GlcNAc, N-acetyl glucose, HA, hemagglutinin; NA, neuraminidase; HEF, hemagglutinin–esterase (acetylesterase)-fusion, HE, hemagglutinin–esterase (acetylesterase); TGEV, transmissible gastroenteritis virus; BCoV, bovine coronavirus; HCoVOC43, human coronavirus OC43; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; IBV, infectious bronchitis virus; HPIV1, human parainfluenza virus 1; VP1, viral protein 1; VP4, viral protein 4; DAF/CD55, complement regulatory protein decay-accelerating factor; GM1, monosialotetrahexosylganglioside; DAF, decay-accelerating factor.

Figure 2

Flowchart showing that increased sialic acid level in plasma predicts diabetic nephropathy. RBC, red blood cell.

Table 2

Potential therapeutic targets and effects and mechanism of action of sialic acid in various diseases

DiseaseDrug or potential therapeutic targetTherapeutic effectsMechanism of actionRefs.
Alzheimer diseaseHuman β-amyloid SA-binding lectin LFADecrease in amyloid plaque deposition in the brain, reducing neuroinflammationBinding to gangliosides in neuronal lipid rafts and inhibiting the binding of amyloid peptides[109]
CVD

  1. Quercetin 7-O-SA

  2. Neuraminidase inhibitors (oseltamivir and zanamivir)

Antioxidation, antiinflammation, cholesterol efflux, promotion of biomolecule protection, prevention of CAD progressionAntioxidant, antiatherosclerosis, decreased hydrogen peroxide, reduced expression of TNF-α, MCP-1, ICAM-1, VCAM-1, reducing Neu5Ac levels by inhibiting its regulatory enzyme (neuraminidase)[90, 60]
Cancer

  1. SA/mPEG AuNPs

  2. EPI-SL

  3. PSA-TPGS

  4. SA-imprinted BS-NPs

  5. Blockade of CD24-Siglec-10 interaction in TNBC and ovarian cancer

  6. Combination of sialic acid analog, HDI, and anti-GD2 antibody (dinutuximab) in neuroblastoma

  7. Fluorinated sialic acids (e.g., Ac53Fax Neu5Ac)

Inhibiting the evasion of the immune response, improvement of the tumor-targeting efficiency and antitumor activity, improvement in immune responses, enhancement of cell cytotoxicity, clearance of cancer cells by macrophages, localized blockade of tumor antigens

  1. Evasion of the reticuloendothelial system

  2. Enhancement endocytosis of liposomes by circulating N/Ms

  3. ABC phenomenon weakness

  4. Cleavage of intracellular GSH

  5. Enhancement of phagocytic activity using monoclonal antibodies targeting CD24-Siglec-10 interaction in ovarian cancer and TNBC

  6. Concurrent increase of sialyltransferase expression involved in GD2 synthesis and blockade of GD2 in neuroblastoma

  7. Repeated injection of fluorinated sialic acids can directly inhibit tumor-associated sialyltransferases in melanoma and neuroblastoma

[41, 50, 52, 55, 110, 111]
Viral infection (chicken new castle, influenza virus, coronavirus, and rotavirus)

  1. Ovomucin

  2. Oseltamivir

Antiviral activity

  1. Unknown

  2. Neuraminidase inhibitors

[93, 112]
Neurological Disorders

  1. SAPPM copolymer for delivering DDS in SCI

  2. Ac3ManNAc for delivering ManNAc-6-P in GNE myopathy

Neuroregeneration, increased neuroprotective capacity, providing substrate for sialic acid biosynthesis

  1. Enhancing the distribution of DDS via binding to E-selectin in SCI

  2. Increase in sialic acid levels via providing the deficient substrate in GNE (IBM2) myopathy

[76, 113, 114]
Rheumatoid arthritis and comorbid tumorsSialic acid-modified doxorubicin hydrochloride liposome (DOX-SAL)Accumulation reduction of inflammatory neutrophils at the disease siteInduction of PBN apoptosis by binding to L-selectin[115]

[i] SA, sialic acid; LFA, Limacus flavus agglutinin; CAD, coronary artery disease; CVD, cardiovascular diseases; TNF-α, tumor necrosis factor-α; MCP-1, monocyte chemoattractant protein-1; ICAM-1, intercellular adhesion molecule-1; VCAM-1, vascular cell adhesion molecule-1; mPEG, methoxy polyethylene glycol; AuNPs, gold nanoparticles; EPI-SL, SA-stearic acid conjugates and epirubicin-loaded liposomes; N/Ms, neutrophils and monocytes; PSA-TPGS, polysialic acid and d-α-tocopheryl polyethylene glycol 1000 succinate conjugates; ABC, accelerated blood clearance; BS-NPs, biodegradable silica nanoparticles; GSH, glutathione; Siglec-10, sialic acid-binding immunoglobulin-type lectins; TNBC, triple-negative breast cancer; SAPPM, sialic acid-polyethylene glycolpoly (lactic-co-glycolic acid); DDS, drug-delivery system; SCI, spinal cord injury; Ac3ManNAc, 1,3,4-O-acetylated N-acetylmannosamine; ManNAc-6-P, N-acetylmannosamine 6-phosphate, PBN, peripheral blood neutrophil; HDI, histone deacetylase inhibitors.

Table 3

Various methods for sialic acid detection

MethodExampleAdvantagesDisadvantagesRefs.
Biochemical assayResorcinol assayAssays bound and free SAConsiderable interferences by pentoses, hexoses, and uronic acids[116]
Periodate–thiobarbituric acid assayAssays free SAConsiderable interferences by 2-deoxyribose, unsaturated fatty acids, lactose, and maltose Bound SA not detected[117]
Roboz assayAssays bound and free SA
Eliminates interferences such as deoxyribose, fatty acids, and some neutral carbohydrates		Slight turbidity in the assay solution[118]
Periodic acid/MBTHAssays total SA without release sialic acids by acid hydrolysis or neuraminidase treatment,Considerable interferences[119, 120]
Acidic ninhydrin assayAssays bound and free SAConsiderable interferences[121, 122]
Enzymatic and fluorometric assayMeasurement total[123]
Neu5Ac
Simple and convenient
No significant cross-reactivity or interference
Enzymatic and calorimetric assayMeasurement total[123,124,125]
Neu5Ac
Simple and convenient
No significant cross-reactivity or interference
HPLC fluorescent detectionHigh specificityExpensive, research use only[125]
ELISA and calorimetric assayHigh specificityResearch use only[56]

[i] SA, sialic acid; MBTH, 3-methyl-2-benzothiazolone hydrazone assay, HPLC, high-performance liquid chromatography; ELISA, enzyme-linked immunosorbentassay.

Table 4

Diagnostic parameters for sialic acid

Target diseaseDetection methods for SATarget tissueSensitivity (%)Specificity (%)Cut-offAUC (%)Refs.
Breast cancerSurface-enhanced
Raman spectroscopy		Saliva809312 mg/dL95[127]
Breast cancerSurface-enhanced
Raman spectroscopy		Saliva8010015.5 mg/dL94.05[128]
Rheumatoid arthritisHPLCSerum84.292766.70 μg/mL92.1[126]
Nasopharynx cancerEnzymatic methodSerum30.9583.33≥650 mg/dL80.7[129]
COVID-19 and gastrointestinal tractELISASerum76.273.774.55 mg/dL84[130]
Oral squamous cell carcinomaSpectrophotometric methodSaliva100100>0.30 μg/mL100[131]
Blood93.33100>4.23 μg/mL98.3

[i] SA, sialic acid; AUC, area under the receiver operating characteristic curve; HPLC, high-performance liquid chromatography; COVID-19; coronavirus disease 2019; ELISA, enzyme-linked immunosorbent assay.

DOI: https://doi.org/10.2478/abm-2022-0020 | Journal eISSN: 1875-855X | Journal ISSN: 1905-7415
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Language: English
Page range: 153 - 167
Published on: Aug 31, 2022
Published by: Chulalongkorn University
In partnership with: Paradigm Publishing Services
Keywords:
cardiovascular diseases,
diabetic nephropathies,
molecular targeted therapy,
neoplasms,
neuraminic acids,
sialic acid,
virus diseases
Related subjects:
Medicine,
Assistive professions, nursing,
Basic medical science,
Basic medical science, other,
Clinical medicine,
Clinical medicine, other

© 2022 Aida Doostkam, Leila Malekmakan, Alireza Hosseinpour, Sahar Janfeshan, Jamshid Roozbeh, Fatemeh Masjedi, published by Chulalongkorn University
This work is licensed under the Creative Commons Attribution 4.0 License.

Volume 16 (2022): Issue 4 (August 2022)
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