Abstract
Human Ezrin Peptides (HEPs) are inhibitors of expression of IL-6 and other inflammatory cytokines, amplifiers of adaptive B cell and T cell immunity and enhancers of tissue repair. The mutation stable C-terminus of HIV gp120, mimics 69% of the “Hep-receptor”, a zipped α-helical structure in the middle of the α domain of human ezrin protein. Synthetic peptides homologous to the Hep-receptor of ezrin of five to fourteen amino acids, activate anti-viral immunity against a wide range of viruses (HIV, HCV, herpes, HPV, influenza and other human respiratory viruses). Human Ezrin Peptide One (HEP1) TEKKRRETVEREKE (brand name Gepon, registered for human use in Russia from 2001) is a successful treatment for opportunistic infections in HIV-infected patients. That treats HEP1and prevents mucosal candidiasis, herpes zoster outbreaks and infection-induced chronic diarrhea. There are clinical publications in Russian on the successful treatments of chronic recurrent vaginal candidiasis, acute and chronic enterocolitis and dysbacteriosis, which are accompanied by normalization of the mucosal microbiome, and the decline or disappearance of inflammation. HEP1 is also an effective treatment and prevention for recurrent inflammation and ulceration in the stomach, duodenum and colon. HEP1 and RepG3 GEKKRRETVEREGG (a derivative of HEP1) have been used successfully as an inhaled spray peptide solution to treat a small number of human volunteers with mild-to-moderate COVID, resulting from SARS-CoV-2 infection, based on earlier successes in treating acute viral respiratory disease with inflammatory complications. Ezrin peptides seem to correct a dysregulation of innate immune responses to SARS-CoV-2. They are also adjuvants of B cell adaptive immunity and increase antibody titres, resulting in protection from lethal virus infection of mice. In a clinical study in Moscow, orally administered HEP1 was shown to enhance antibody-titres produced in response to hepatitis-B vaccination. These very preliminary but promising results with ezrin peptide treatment of COVID must be replicated in large-scale randomised placebo controlled clinical studies, to be verified.
Highlights
The ideal therapy should correct the dysfunction of the innate immune response to SARS-CoV-2 which leads to excess inflammation and over-expression of IL-6, as well as enhancing adaptive immune responses to resolve the infection and prevent re-infection [10,11]
Our current hypothesis for the mechanism of action of ezrin peptides, is they act on a “receptor” conformation of human ezrin, in which the ezrin α domain is exposed on the external surface of the cell-membrane of lymphocytes, epithelial cells, fibroblasts, monocytes and macrophages
Mouse-monoclonal anti-ezrin antibody (6F1A9), raised to a recombinant fragment corresponding to human-ezrin amino-acids 292–464 containing the Hep-receptor and part of the α domain expressed in E
Summary
There is a great need for a safe, effective, cheap and reliable therapy for acute and chronic COVID disease induced by SARS-CoV-2 infection. It is well established that high levels of inflammation and IL-6 expression in response to SARS-CoV-2 infection predicts severe COVID-19 and death [1,2,3]. It has been demonstrated that 2019 SARS-CoV-2 spike protein subunit 1 (CoV2-S1) induces high levels of NF-κB activation, production of pro-inflammatory cytokines and epithelial damage in human bronchial epithelial cells [BCiNS1.1 cell line] [2]. SARS-CoV-2 infection or spike protein expression in human epithelial cells [Huh7.5 and A549 cell lines] inhibits ACE2 expression leading to the induction of AT1 signalling, and promotion of IL-6/soluble IL-6R release [4]. The match of the amino-acid side chain charges and secondary structure suggested the HIV gp120 and human ezrin sequences have related functions [17,18,19,20,21]
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