The Role of Heparin in COVID-19: An Update after Two Years of Pandemics

Mangiafico, Marco; Caff, Andrea; Costanzo, Luca

doi:10.3390/jcm11113099

Cited by 16 publications

(15 citation statements)

References 83 publications

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“… 4 , 6 These observations have generated interest in developing heparin as a therapeutic for SARS-CoV-2 infections. 5 , 15 , 16 , 38 , 39 Its use is, however, complicated by the structural heterogeneity and the risk of causing bleeding and thrombocytopenia. Therefore, there is an urgent need to develop well-defined heparin mimetics that can potently inhibit viral cell binding with reduced side effects.…”

Section: Discussionmentioning

confidence: 99%

“…Therapeutics may also reduce the prevalence of long-covid, which is associated with both hospitalized patients and those with mild or moderate disease. Earlier studies have demonstrated that SARS-CoV-2 employs HS for initial cell attachment and enzymatic removal of HS resulted in a very substantial reduction in cell binding and infectivity. , These observations have generated interest in developing heparin as a therapeutic for SARS-CoV-2 infections. ,,,, Its use is, however, complicated by the structural heterogeneity and the risk of causing bleeding and thrombocytopenia. Therefore, there is an urgent need to develop well-defined heparin mimetics that can potently inhibit viral cell binding with reduced side effects.…”

Section: Discussionmentioning

confidence: 99%

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Well-Defined Heparin Mimetics Can Inhibit Binding of the Trimeric Spike of SARS-CoV-2 in a Length-Dependent Manner

Sun

Chopra

Tomris

et al. 2023

JACS Au

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The emergence of new SARS-CoV-2 variants and the dangers of long-covid necessitate the development of broad-acting therapeutics that can reduce viral burden. SARS-CoV-2 employs heparan sulfate (HS) as an initial cellular attachment factor, and therefore, there is interest in developing heparin as a therapeutic for SARS-CoV-2. Its use is, however, complicated by structural heterogeneity and the risk of causing bleeding and thrombocytopenia. Here, we describe the preparation of well-defined heparin mimetics by a controlled head-to-tail assembly of HS oligosaccharides having an alkyne or azide moiety by copper-catalyzed azide-alkyne cycloaddition (CuAAC). Alkyne- and azide-containing sulfated oligosaccharides were prepared from a common precursor by modifying an anomeric linker with 4-pentynoic acid and by enzymatic extension with an N -acetyl-glucosamine having an azide moiety at C-6 (GlcNAc6N 3 ), respectively, followed by CuAAC. The process of enzymatic extension with GlcNAc6N 3 followed by CuAAC with the desired alkyne-containing oligosaccharides could be repeated to give compounds composed of 20 and 27 monosaccharides, respectively. The heparin mimetics could inhibit the binding of the SARS-CoV-2 spike or RBD to immobilized heparin or to Vero E6 cells. The inhibitory potency increased with increasing chain length, and a compound composed of four sulfated hexasaccharides linked by triazoles had a similar potency as unfractionated heparin. Sequence analysis and HS microarray binding studies with a wide range of RBDs of variants of concern indicate that they have maintained HS-binding capabilities and selectivities. The heparin mimetics exhibit no or reduced binding to antithrombin-III and platelet factor 4, respectively, which are associated with side effects.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Well-Defined Heparin Mimetics Can Inhibit Binding of the Trimeric Spike of SARS-CoV-2 in a Length-Dependent Manner

Sun

Chopra

Tomris

et al. 2023

JACS Au

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“…Of biological relevance, either possibility suggests the application of heparan sulphate mimetics as anti-viral therapies. Indeed, soluble GAGs, especially heparin mimetics, have been used as competitive inhibitors to block Coronavirus infection [13][14][15] . Of relevance, the LMW-DS used in this study, ILB®, acts as a soluble heparin mimetic that can offer a competitive binding site for heparin-binding moieties, thereby preventing receptor interactions 16 .…”

Section: Discussionmentioning

confidence: 99%

A clinical stage LMW-DS drug inhibits cell infection by coronaviruses and modulates reactive cytokine release from microglia

Logan

Mazzon

Bruce

et al. 2022

Preprint

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Most coronaviruses infect animals including bats, birds and mammals, which act as hosts and reservoirs for the viruses, but the viruses can sometimes move host species and infect humans. Coronoviruses were first identified as human pathogens in the 1960s and now there are seven types known to infect humans. Whilst four of these types cause mild-to-moderate respiratory disease, the other three may cause more severe and possibly even fatal disease in vulnerable individuals particularly, with the most recent SARS-CoV-2 pandemic being associated with severe acute respiratory syndrome (SARS) in many infected people. The aim of the present study was to evaluate the potential of a unique low molecular weight dextran sulphate (LMW-DS) clinical stage drug, ILB®, to inhibit infection of human cells by the NL63 coronavirus assessed by immunofluorescence of viral particles, and also to see if the drug directly blocked the interaction of the SARS-CoV-2 viral spike protein with the ACE2 receptor. Furthermore, we evaluated if ILB® could modulate the downstream consequences of viral infection including the reactive cytokine release from human microglia induced by various SARS-CoV-2 variant spike proteins. We demonstrated that ILB® blocked ACE2:spike protein interaction and inhibited coronaviral infection. ILB® also attenuated the omicron-induced release of pro-inflammatory cytokines, including TNFα, from human microglia, indicating control of post-viral neuroinflammation. In conclusion, given the safety profile of ILB® established in a number of Phase I and Phase II clinical trials, these results highlight the potential of ILB® to treat patients infected with coronaviruses to both limit infectivity and attenuate the progression to severe disease. There is now an opportunity to translate these findings quickly by the clinical investigation of drug efficacy.

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“…Lastly, Mangiafico and co-workers [19] reviewed the pathophysiology of vascular damage and the hypercoagulative state related to SARS-CoV-2 infection and the role of heparin in various COVID-19 clinical settings according to the most recent evidence [20][21][22][23][24]. Authors concluded that the prophylactic dose of heparin is recommended in all hospitalized patients unless contraindicated, while the therapeutic dose could be considered in nonpregnant patients requiring low-flow supplemental oxygen, with increased D-dimer levels and low bleeding risk [25][26][27].…”

mentioning

confidence: 97%

“…In the last two years, the new coronavirus has afflicted the whole world causing a pandemic burdened by high morbidity and mortality [1]. Over recent months, increasing evidence has been brought to light that venous thromboembolism (VTE) was a frequent complication that adversely affected the clinical course of the coronavirus disease 2019 (COVID- 19), especially in the most severe cases [2]. Consequently, numerous researchers around the world have focused efforts on identifying the underlying etiopathogenetic mechanisms of vascular involvement in COVID-19 and on potential therapies that can improve the outcome on these patients.…”

mentioning

confidence: 99%