Long COVID, also referred to as Post-Acute Sequelae of COVID (PASC), is probably triggered during SARS-CoV-2 infection and acute COVID-19 by SARS-CoV-2 Spike-protein binding and hyper-activating the cell-membrane expressed Receptor for Advance Glycation End-products (mRAGE) and Toll-Like Receptor 4 (TLR4). SARS-CoV-2 infects lung monocytes by Spike binding to mRAGE (not ACE2). During acute COVID-19, high levels of IL-6 hyper-stimulate S100A8/A9 expression and secretion. Although no viral protein nor mRNA can be detected in half of long COVID (PASC) patients, there is a significant elevation of serum levels of IL-1b, IL-6, TNFa, and S100A8/A9. It appears that a pathological pro-inflammatory feedback loop (the TLR4/RAGE-loop) is established during acute COVID-19, which is maintained by S100A8/A9 > RAGE/TLR4 chronic inflammatory signalling, even after SARS-CoV-2 has been cleared from the body. During long COVID/PASC, Ca2+-binding protein S100A8/A9 chronically stimulates TLR4/RAGE-signalling to induce chronic expression of IL-1b, IL-6 and TNFa. Secreted IL-6 binds to its IL-6R receptor on the surface of other cells and signals via STAT3 and C/EBPb for more S100A8/A9 expression. Secreted IL-1b binds to its receptor IL-1R on other cells, and signals via NFkB for more mRAGE and TLR4 expression. New S100A8/A9 can bind and activate cell-surface mRAGE and TLR4 to stimulate expression of more IL-1b, IL-6 and TNFa. This process establishes a pathogenic pro-inflammatory TLR4/RAGE-loop: IL-1b + IL-6 > IL-1R + IL-6R > TLR4/mRAGE + S100A8/A9 > IL-1b + IL-6, which generates multi-organ inflammation that persists in the blood vessels, the brain, the liver, the heart, the kidneys, the gut and the musculo-skeletal system, and is responsible for all the complex pathologies associated with long COVID/PASC. Chronic expression of IL-1, IL-6 and TNFa is critical for the maintenance of the TLR4/RAGE-loop and persistence of long COVID/PASC. Ezrin peptides are inhibitors of IL-1, IL-6, IL-8 and TNFa expression, so are now being investigated as potential therapy for long COVID/PASC. There is preliminary anecdotal evidence of symptomatic relief (not confirmed yet by formal clinical trials) from a few long COVID/PASC patient volunteers, after treatment with ezrin peptide therapy.

This report shows the therapeutic benefit of HEP1 (human ezrin peptide 324-337; TEKKRRETVEREKE) monotherapy of hepatitis C virus (HCV) infection in HIV infected patients in two clinical studies. In the Pilot Study I, 16 of 18 patients responded well to the treatment with significant reductions of HCV viral load and a normalization of serum liver enzymes. In 8 of 18 patients, HCV RNA became undetectable, and 3 of 8 interferon/ribavirin treatment failure patients showed undetectable HCV load following HEP1 treatment. In the second study, 8 of 10 patients responded well to the treatment with a pronounced reduction of the HCV viral load and a normalization of serum liver enzymes. Three of 15 patients (20%) showed an undetectable viral load 30 days after the end of a 30-day course of HEP1 treatment. In both studies, all genotypes of HCV were sensitive to HEP1 treatment. Analysis of the combined data from both studies showed the overall efficacy of HEP1 therapy: in 37 HCV+HIV patients, HEP1 therapy gave the following results: 10 of 37 (27%) HCV+HIV patients showed a reduction of viral load between -7 log (-10,000,000x) and -3 log (-1000x); 4 of 37 (11%) a reduction of -3 log (-1000x); 6 of 37 (16%) a reduction of -2 log (-100x); 11 of 37 (30%) a reduction of -1 log (-10x); 6 of 37 (16%) a reduction of less than -1 log (-10x); 0 of 37 (0%) had an increase in viral load, and the average reduction in viral load for all 37 patients was -2 log (-100x). No adverse reactions or side effects were detected and the improving CD4/CD8 ratio showed that the therapy had no negative impact on the immunological status. Thus, oral HEP1 therapy matches the efficacy results for injectable peginterferon/oral ribavirin therapy with the advantages of more rapid action and less side effects. HEP1 therapy should be used in patients where either peginterferon/ribavirin therapy fails or is contraindicated.

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.

SARS-CoV-2 infection inhibits interferon expression, while hyper-activating innate-immune signalling and expression of pro-inflammatory cytokines. SARS-CoV-2 proteins: Spike, M and nsp6, nsp12 and nsp13 inhibit IFR3-mediated Type-1-interferon defence, but hyper-activate intracellular signalling, which leads to dysfunctional expression of pro-inflammatory cytokines, particularly IL-1β IL-6, IL-8, and TNFα. Ezrin, a sub-membrane adaptor-protein, organises multi-protein-complexes such as ezrin+NHERF1+NHE+CFTR, which control the density and location of ACE2 receptor expression on the luminal surface of airway-epithelial-cells, as well as determining susceptibility to SARS-CoV-2 infection. This protein complex is vital for lung-surfactant production for efficient gas-exchange. Ezrin also forms multi-protein-complexes that regulate signalling kinases; Ras, PKC, PI3K, and PKA. m-RAGE is a pattern-recognition-receptor of the innate immune system that is triggered by AGEs, which are chemically modified proteins common in the elderly and obese. m-RAGE forms multi-protein complexes with ezrin and TIRAP, a toll-like-receptor adaptor-protein. The main cause of COVID-19 is not viral infection but pro-inflammatory p38MAPK signalling mediated by TLRs and RAGE. In contrast, it appears that activated ezrin+PKA signalling results in the activation of transcription-factor CREB, which suppresses NFκB mediated pro-inflammatory cytokine expression. In addition, competition between ezrin and TIRAP to form multi-protein-complexes on membrane PIP2-lipid-rafts is a macromolecular-switch that changes the priority from innate immune activation programs to adaptive immune activation programs. Human Vasoactive Intestinal Peptide (VIP), and Human Ezrin Peptides (HEP-1 and RepG3) probably inhibit COVID-19 by activating the ezrin+PKA and ras>Raf>MEK>ERK>RSK>CREB>IL-10 signalling, which favours activation of adaptive immunity programs and inhibition of the dysfunctional innate-inflammation, the cause of COVID-19. HEP-1, RepG3, and VIP in individual human volunteers and in small clinical studies have been shown to be effective COVID-19 therapies, and seem to have a closely related mechanism of action.