HIF Prolyl Hydroxylase Inhibitors for COVID-19 Treatment: Pros and Cons

Poloznikov, Andrey; Nersisyan, Stepan; Hushpulian, Dmitry M.; Kazakov, Eliot H.; Tonevitsky, Alexander G.; Казаков, С. В.; Вечорко, В.И.; Никулин, С. В.; Makarova, J. A.; Gazaryan, Irina G.

doi:10.3389/fphar.2020.621054

Cited by 22 publications

(16 citation statements)

References 89 publications

(89 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Together, these results indicate that the hypoxia response governed by HIF-1α in the host target cells leads to a protective effect against SARS-CoV-2 infection. In this context, the administration of HIF prolyl-hydroxylase (PHD) inhibitors that result in accumulation of HIF-1α may serve as a potential treatment to limit the initial attachment and entry of the virus into host cells [38,39]. It should be noted that as the infection progresses into COVID-19 disease, exacerbated inflammatory responses contribute to severity.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia reduces cell attachment of SARS-CoV-2 spike protein by modulating the expression of ACE2, neuropilin-1, syndecan-1 and cellular heparan sulfate

Prieto-Fernández

Egia-Mendikute

Vila-Vecilla

et al. 2021

Emerging Microbes & Infections

View full text Add to dashboard Cite

A main clinical parameter of COVID-19 pathophysiology is hypoxia. Here we show that hypoxia decreases the attachment of the receptor binding domain (RBD) and the S1 subunit (S1) of the spike protein of SARS-CoV-2 to epithelial cells. In Vero E6 cells, hypoxia reduces the protein levels of ACE2 and neuropilin-1 (NRP1), which might in part explain the observed reduction of the infection rate. In addition, hypoxia inhibits the binding of the spike to NCI-H460 human lung epithelial cells by decreasing the cell surface levels of heparan sulfate (HS), a known attachment receptor of SARS-CoV-2. This interaction is also reduced by lactoferrin, a glycoprotein that blocks HS moieties on the cell surface. The expression of syndecan-1, an HS-containing proteoglycan expressed in lung, is inhibited by hypoxia on a HIF-1α-dependent manner. Hypoxia or deletion of syndecan-1 results in reduced binding of the RBD to host cells. Our study indicates that hypoxia acts to prevent SARS-CoV-2 infection, suggesting that the hypoxia signaling pathway might offer therapeutic opportunities for the treatment of COVID-19.

show abstract

Section: Discussionmentioning

confidence: 99%

Hypoxia reduces cell attachment of SARS-CoV-2 spike protein by modulating the expression of ACE2, neuropilin-1, syndecan-1 and cellular heparan sulfate

Prieto-Fernández

Egia-Mendikute

Vila-Vecilla

et al. 2021

Emerging Microbes & Infections

View full text Add to dashboard Cite

show abstract

“…Together, these results indicate that the hypoxia response governed by HIF-1α leads to a protective effect against SARS-CoV-2 infection. In this context, the administration of HIF prolyl-hydroxylase inhibitors (PHD) that gives place to the accumulation of HIF-1α may serve as a potential treatment of COVID-19 [32,33].…”

Section: Discussionmentioning

confidence: 99%

Hypoxia reduces cell attachment of SARS-CoV-2 spike protein by modulating the expression of ACE2, neuropilin-1, syndecan-1 and cellular heparan sulfate

Prieto-Fernández

Egia-Mendikute

Vila-Vecilla

et al. 2021

Preprint

View full text Add to dashboard Cite

A main clinical parameter of Covid-19 pathophysiology is hypoxia. Here we show that hypoxia decreases the attachment of the receptor binding domain (RBD) and the S1 subunit (S1) of the spike protein to epithelial cells. In Vero E6 cells, hypoxia reduces the protein levels of ACE2, which might in part explain the observed reduction of the infection rate. However, hypoxia also inhibits the binding of the spike to human lung epithelial cells lacking ACE2 expression, indicating that hypoxia modulates the expression of additional binding partners of SARS-CoV-2. We show that hypoxia also decreases the total cell surface levels of heparan sulfate, a known attachment receptor of SARS-CoV-2, by reducing the expression of syndecan-1 and syndecan3, the main proteoglycans containing heparan sulfate. Our study indicates that hypoxia acts to prevent SARS-CoV-2 infection, suggesting that the hypoxia signaling pathway might offer therapeutic opportunities for the treatment of Covid-19.

show abstract

“…In normoxic conditions, a balanced proteasomal degradation of constitutively expressed HIF-1α induced by 2ODD abrogates the translocation of HIF-1α and HIF-β dimer to activate HRE transcription. However, in a hypoxic scenario the balance of 2ODD and HIF-1α skews towards overproduction of HIF-1α, leading to dimerization with HIF-β and transcriptional activation of HRE 22 . Higher levels of HIF-α have also been shown to induce higher expression of angiotensin-converting enzyme-2 (ACE-2) receptor on cell surface facilitating the viral entry in the case of SARS-CoV-2.…”

Section: Discussionmentioning

confidence: 99%

C allele of rs479200 of the host EGLN1 gene - a risk factor for severe COVID-19 (pilot study)

Harit

Singh

et al. 2022

Preprint

View full text Add to dashboard Cite

Background Coronavirus disease-2019 (COVID-19) symptoms can range from asymptomatic, moderate to severe manifestations that result in an overall global case fatality rate of 2-7 %. While each variant has had it challenges, and some variants are more severe than others, risk factors of severe COVID-19 are still under investigation. In this context, the host genetic predisposition is also a crucial factor to investigate. In the present study, we investigated host genotypes of the SNP rs479200 of the host EGLN1 gene, previously implicated in high altitude pulmonary edema (HAPE), some of whose symptoms such as hypoxia profoundly overlap with severe COVID-19. Methods After informed consent, 158 RT-PCR confirmed COVID-19 patients (March 2020 to June 2021) were enrolled in the study. Based on their clinical manifestations, disease severity was categorized by the clinical team. Blood samples were drawn and DNA was extracted from the clot to infer different genotypes of the SNP rs479200 of the host EGLN1 gene. PCR-RFLP analysis of the SNP rs479200 (C > T) was performed with an amplicon size of 367 bp. Various genotypes (TT, TC and CC) were assigned based on the presence/absence of a restriction site (T/GTACA) for restriction enzyme BsrGI. Allele frequencies, Hardy-Weinberg Equilibrium (HWE) and multinomial logistic regression were performed using statistical tool SPSS version 23 (IBM). Findings We observed that the severe COVID-19 category was composed of comparatively younger patients with mean age (34.9), compared to asymptomatic and moderate categories whose mean age was 49.7 and 54.3, respectively. Preponderance of males and high heterozygosity (TC) was observed across the clinical categories. Notably, the frequency of C allele (0.664) was 2-fold higher than the T allele (0.336) in severe COVID-19 patients, whereas the allele frequencies were similar in asymptomatic and moderate category of COVID-19 patients. Multinomial logistic regression showed an association of genotypes with increasing clinical severity; odds ratio (adjusted OR- 11.414 (2.564-50.812)) and (unadjusted OR- 6.214 (1.84-20.99)) for the genotype CC in severe category of COVID-19. Interestingly, the TC genotype was also found to be positively associated with severe outcome (unadjusted OR-5.816 (1.489-22.709)), indicating association of C allele in imparting the risk of severe outcome. Interpretation The study provides strong evidence that the presence of C allele of SNP (rs479200) of the EGLN1 gene associates with severity in COVID-19 patients. Thus, the presence of C allele may be a risk factor for COVID-19 severity. This study opens new avenues towards risk assessment that include EGLN1 (rs479200) genotype testing and identifying patients with C allele who might be prioritized for critical care.

show abstract

HIF Prolyl Hydroxylase Inhibitors for COVID-19 Treatment: Pros and Cons

Cited by 22 publications

References 89 publications

Hypoxia reduces cell attachment of SARS-CoV-2 spike protein by modulating the expression of ACE2, neuropilin-1, syndecan-1 and cellular heparan sulfate

Hypoxia reduces cell attachment of SARS-CoV-2 spike protein by modulating the expression of ACE2, neuropilin-1, syndecan-1 and cellular heparan sulfate

Hypoxia reduces cell attachment of SARS-CoV-2 spike protein by modulating the expression of ACE2, neuropilin-1, syndecan-1 and cellular heparan sulfate

C allele of rs479200 of the host EGLN1 gene - a risk factor for severe COVID-19 (pilot study)

Contact Info

Product

Resources

About