Glycosaminoglycan Compositional Analysis of Relevant Tissues in Zika Virus Pathogenesis and in Vitro Evaluation of Heparin as an Antiviral against Zika Virus Infection

Abstract

Zika virus (ZIKV) is an enveloped RNA virus from the flavivirus family that can cause fetal neural abnormalities in pregnant women. Previously, we established that ZIKV-EP (envelope protein) binds to human placental chondroitin sulfate (CS), suggesting that CS may be a potential host cell surface receptor in ZIKV pathogenesis. In this study, we further characterized the GAG disaccharide composition of other biological tissues (i.e., mosquitoes, fetal brain cells, and eye tissues) in ZIKV pathogenesis to investigate the role of tissue specific GAGs. Heparan sulfate (HS) was the major GAG, and levels of HS-6-sulfo, HS 0S (unsulfated HS), and CS 4S disaccharides were the main differences in the GAG composition of Aedes aegypti and Aedes albopictus mosquitoes. In human fetal neural progenitor and differentiated cells, HS 0S and CS 4S were the main disaccharides. A change in disaccharide composition levels was observed between undifferentiated and differentiated cells. In different regions of the bovine eyes, CS was the major GAG, and the amounts of hyaluronic acid or keratan sulfate varied depending on the region of the eye. Next, we examined heparin (HP) of various structures to investigate their potential in vitro antiviral activity against ZIKV and Dengue virus (DENV) infection in Vero cells. All compounds effectively inhibited DENV replication; however, they surprisingly promoted ZIKV replication. HP of longer chain lengths more strongly promoted activity in ZIKV replication. This study further expands our understanding of role of GAGs in ZIKV pathogenesis and carbohydratebased antivirals against flaviviral infection.O nce believed to be a benign virus, Zika virus (ZIKV) has cumulatively led to >200000 infections resulting in a global health risk, especially in pregnant women. ZIKV is an

Heparin: A simplistic repurposing to prevent SARS-CoV-2 transmission in light of its in-vitro nanomolar efficacy

“…Many other viruses are sensitive to heparin & sulfated polysaccharides [ 38 ]. Type of heparin Assay format Efficacy Proposed usage Pathogen References Comments UFH Cellular cytopathogenicity 50% cytopathogenic reduction at 7.5 μg/ml Therapeutic HIV [ 39 , 40 ] No toxicity at a concentration up to 400 μg/ml Various forms of heparin plaque inhibition assay and viral reduction assay with Vero cells NA NA ZIKV [ 41 ] Promoted ZIKV replication. The longer the heparin chain, the stronger the replication promotion Various forms of heparin plaque inhibition assay and viral reduction assay with Vero cells Up to 93.5% inhibition at 200 μg/ml Therapeutic DENV [ 42 , 43 ] All formulations of heparin used in the study inhibited DENV replication Biomimetic heparins Plaque inhibition assay with vero and 293TT cells IC50 varied from 0.50–2.88 μg/ml Therapeutic HSV; HPV; RSV; ROTV [ 44 ] All of the studied viruses are heparan sulfate dependent …”

Heparan Sulfate Proteoglycans and Viral Attachment: True Receptors or Adaptation Bias?

“…An additional study showed that HSPG are present in mosquitoes and in different human anatomical sites known to be efficiently infected by ZIKV. Nevertheless, when the virus was pre-incubated with different heparin variants, not only there was no protection, but the viral titer was also increased [188].…”

The Prediction of miRNAs in SARS-CoV-2 Genomes: hsa-miR Databases Identify 7 Key miRs Linked to Host Responses and Virus Pathogenicity-Related KEGG Pathways Significant for Comorbidities

“…Endogenous HERV-K furthermore binds to heparin for cell entry [80], and, while heparin has been found to further Zika virus infection, it acts as an antiviral against Dengue replication [81]. Heparin sulphate is identified as an inhibitory regulator of porcine epidemic diarrhoea virus infection [82] and acts as an attachment factor for rabies virus entry and infection [83], as well as an enhancer of Nipah and Hendra virus infections, which are highly pathogenic, zoonotic paramyxoviruses [84]. This highlights the importance of this KEGG pathway both in human, zoonotic and veterinary viral infections.…”