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

Andrey A Poloznikov,Alexander G Tonevitsky,Eliot H Kazakov,Julia A Makarova,Stepan A Nersisyan,Irina G Gazaryan,Dmitry M Hushpulian,Sergey V Kazakov,Sergey V Nikulin,Valery I Vechorko

doi:10.3389/fphar.2020.621054

Abstract

The review analyzes the potential advantages and problems associated with using HIF prolyl hydroxylase inhibitors as a treatment for COVID-19. HIF prolyl hydroxylase inhibitors are known to boost endogenous erythropoietin (Epo) and activate erythropoiesis by stabilizing and activating the hypoxia inducible factor (HIF). Recombinant Epo treatment has anti-inflammatory and healing properties, and thus, very likely, will be beneficial for moderate to severe cases of COVID-19. However, HIF PHD inhibition may have a significantly broader effect, in addition to stimulating the endogenous Epo production. The analysis of HIF target genes reveals that some HIF-targets, such as furin, could play a negative role with respect to viral entry. On the other hand, HIF prolyl hydroxylase inhibitors counteract ferroptosis, the process recently implicated in vessel damage during the later stages of COVID-19. Therefore, HIF prolyl hydroxylase inhibitors may serve as a promising treatment of COVID-19 complications, but they are unlikely to aid in the prevention of the initial stages of infection.

Highlights

In 2019, a spike in the cases of lethal pneumonia caused by the global spread of the SARS-CoV-2 virus led to an urgent need to develop effective therapies, especially vaccines (Chan et al, 2020; Zhou et al, 2020)
If we focus on the HIFpathway only, as it is the best studied program launched by a hypoxia inducible factor (HIF) PHD inhibitor, some concerns will arise with respect to the initial steps of viral infection
HIF prolyl hydroxylase inhibitors were recently named among candidate drugs for trials in COVID-19 patients (Del Vecchio and Locatelli, 2020)

Summary

Introduction

In 2019, a spike in the cases of lethal pneumonia caused by the global spread of the SARS-CoV-2 virus led to an urgent need to develop effective therapies, especially vaccines (Chan et al, 2020; Zhou et al, 2020). HIF prolyl hydroxylase inhibitors are known to boost endogenous erythropoietin (Epo) and activate erythropoiesis by stabilizing and activating the hypoxia inducible factor (HIF). Hydroxylation appears to be the main regulator of HIFα protein stability and is controlled by non-heme iron α-ketoglutarate dependent dioxygenases known as HIF prolyl hydroxylases (HIF PHD).

Results

Conclusion