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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: Aida Doostkam,  Leila Malekmakan,  Alireza Hosseinpour,  Sahar Janfeshan,  Jamshid Roozbeh and  Fatemeh Masjedi  
Open Access
|Aug 2022

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.

Figure 2

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

Diagnostic parameters for sialic acid

Target diseaseDetection methods for SATarget tissueSensitivity (%)Specificity (%)Cut-offAUC (%)Refs.
Breast cancerSurface-enhancedRaman spectroscopySaliva809312 mg/dL95[127]
Breast cancerSurface-enhancedRaman spectroscopySaliva8010015.5 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

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

  • Quercetin 7-O-SA

  • 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

  • SA/mPEG AuNPs

  • EPI-SL

  • PSA-TPGS

  • SA-imprinted BS-NPs

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

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

  • 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

  • Evasion of the reticuloendothelial system

  • Enhancement endocytosis of liposomes by circulating N/Ms

  • ABC phenomenon weakness

  • Cleavage of intracellular GSH

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

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

  • 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)

  • Ovomucin

  • Oseltamivir

Antiviral activity

  • Unknown

  • Neuraminidase inhibitors

[93, 112]
Neurological Disorders

  • SAPPM copolymer for delivering DDS in SCI

  • Ac3ManNAc for delivering ManNAc-6-P in GNE myopathy

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

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

  • 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]

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 SAEliminates interferences such as deoxyribose, fatty acids, and some neutral carbohydratesSlight 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]

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]
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
Publication frequency: 6 issues per year
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.

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