FORMULATION, USE AND METHOD FOR BROAD-SPECTRUM PROPHYLAXIS AND TREATMENT OF VIRAL INFECTIONS CAUSED BY SARS-CoV-2 AND OTHER EMERGING VIRUSES

Pending Publication Date: 2021-12-23
MELISA INST GENOMICS & PROTEOMICS RES SPA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0010]Zinc (Zn) is a fundamental trace element provided by human diet and the second most abundant essential trace metal after Iron (Maxfield et al 2019; Thambiayya et al 2012). It is well known that over 99% of intracellular zinc is bonded to proteins such as metallothionein, glutathione, histidine, cysteine, and diphosphate compounds (Bozym et al 2006). In addition, because the concentration of intracellular zinc is tightly controlled in human cells by metallothionein (MT), zinc importers (ZIPs), zinc exporters (ZnTs) and specialized storing vesicles, the amount of free Zn2+ ions is extremely limited (Bozym et al 2006; Colvin et al 2008). In fact, it is estimated that intracellular concentration of Zn2+ is in the range of 10 pM to 10 nM. The latter remarks the importance of using active zinc-transporters or zinc-ionophores to induce a transient increase of the intracellular bioavailability of free/labile Zn and potentiate some desired biological effect in target cells (Dabbagh-Bazarbachi et al 2014).
[0011]The role of Zn on viral infections is a topic intensively investigated (Chauteverdi et al 2004; Prasad 2009) For example, in cell culture studies, Zn in combination with ionophore compounds (e.g. pyrithione) that may increase cellular import of free/labile Zn2+ was found to inhibit the replication of various RNA viruses, including rhinovirus, (Krenn et al 2009) influenza virus, (Uchide et al 2002) and respiratory syncytial virus (Suara et al). These studies provided evidence that intracellular Zn2+ levels may affect a common step in the replicative cycle of many viruses. There is clinical evidence that Zn supplementation may shorten the duration and intensity of symptoms of the common cold. One of the first double blind clinical studies by using Zn Gluconate (23 mg) for treatment of common cold, was conducted by Eby et al in 1985. In this study, after 7 days of treatment, 86% of 37 zinc-treated subjects were asymptomatic, compared with only 46% of 28 placebo-treated subjects.
[0012]Despite the obvious lack of clinical evidence about specific effects of Zn on SARS-CoV-2, some experimental evidence suggests that modulation of Zn2+ status may be useful to counteract SARS-CoVs infections (Skalny et al 2020). As discussed above, PLP is essential for virus replication and evasion of innate immunity in host cells (Baéz-Santos et al 2015). In an elegant in vitro study with a fluorogenic inhibitor-screening platform, Han et al (2005) showed that Zn2+ ions were capable of inhibiting PLP protease activity with an IC50 value of 1.3 μM. Two zinc conjugates,

Problems solved by technology

Emerging virus infections continue posing significant public health issues and challenges with the potential to cause epidemics and pandemics.
Although vaccines are one of the most effective measures for infectious disease prophylaxis, unfortunately they are not immediately available to stop a new pathogen.
(Feng et al 2020; Lotfinejad et al 2020; and Yen et al 2020) Unfortunately, these latest public healt

Method used

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  • FORMULATION, USE AND METHOD FOR BROAD-SPECTRUM PROPHYLAXIS AND TREATMENT OF VIRAL INFECTIONS CAUSED BY SARS-CoV-2 AND OTHER EMERGING VIRUSES
  • FORMULATION, USE AND METHOD FOR BROAD-SPECTRUM PROPHYLAXIS AND TREATMENT OF VIRAL INFECTIONS CAUSED BY SARS-CoV-2 AND OTHER EMERGING VIRUSES
  • FORMULATION, USE AND METHOD FOR BROAD-SPECTRUM PROPHYLAXIS AND TREATMENT OF VIRAL INFECTIONS CAUSED BY SARS-CoV-2 AND OTHER EMERGING VIRUSES

Examples

Experimental program
Comparison scheme
Effect test

example 1

EGCG Forms Complexes with Zinc at Physiological pH

[0078]Briefly, a 10 mM EGCG solution was stirred at 750 rpm at 20° C. under the protection of nitrogen. Meanwhile, 10 mM zinc chloride was slowly added to the EGCG solution in a 2:1 molar ratio. The pH of the mixture was adjusted to 7.4 by adding 10 mM NaHCO3. Next, the products formed were collected by centrifugation, washed with deionized water, and lyophilized until the dry EGCG-Zn2+ complex was obtained. The resulting complex was analyzed by FT-IR, with ATR in the range of 800 to 4000 in transmittance, and the absorbance was measured with UV / Vis spectrophotometer, in the range of 190 to 900 nm. We have proposed the formation of at least 3 complex species between EGCG and Zn2+, which are outlined in FIG. 1 and FIG. 4. In addition, changes are observed in the UV-Vis absorption spectra of EGCG compared to the complexes formed, where changes are seen in the 216 nm which are increased in the complexes formed, as seen in FIG. 2. It was...

example 2

EGCG-Zn2+ Complexes Interact with Papain-Like Protease (PLP) of SARS-CoV-2 with more Favorable Energies than EGCG Molecule Alone or Zn Molecule Alone

[0083]Multiple molecular docking analyzes, using 3 conformations of EGCG-Zn2+ complexes and the Papain-like protease of SARS-CoV-2, indicate that the binding energy is favorable (FIG. 5). Considering the conformation of EGCG-Zn2+ complexes 1:1 (1 EGCG: 1 Zn2+), the binding energies obtained was −9.3 Kcal / mol. For the conformation of EGCG-Zn2+ complexes 2:1 (2 EGCG: 1 Zn2+), the binding energies with PLP were −10.1 Kcal / mol. For the conformation of EGCG-Zn2+ complexes 1:2 (1 EGCG: 2 Zn2+), the binding energies with PLP were −9.6 Kcal / mol. Using the same methodology, for the EGCG molecule alone and Zinc gluconate alone, the binding energy with PLP were −8.6 Kcal / mol and −6.0 Kcal / mol, respectively. The binding energies obtained reflect the in-silico feasibility of forming the PLP-EGCG-Zn2+ complexes protein complex (Table 2), producing hy...

example 3

EGCG-Zn2+ Complexes Interact with RNA-Dependent RNA Polymerase Protein (RdRp) of SARS-CoV-2 with more Favorable Energies than EGCG Molecule Alone or Zn Molecule Alone

[0084]New molecular docking analyzes, using 3 conformations of EGCG-Zn2+ complexes and the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2, indicate that the binding energy is favorable (FIG. 6). Considering the conformation of EGCG-Zn2+ complexes 1:1 (1 EGCG: 1 Zn2+), the binding energies obtained were −7.5 Kcal / mol. For the conformation of EGCG-Zn2+ complexes 2:1 (2 EGCG: 1 Zn+2), the binding energies obtained were −9.6 Kcal / mol. For the conformation of EGCG-Zn2+ complexes 1:2 (1 EGCG: 2 Zn2+), the binding energies obtained were −8.3 Kcal / mol. Using the same methodology, for the EGCG molecule alone and Zinc gluconate alone, the binding energy obtained were −7.3 Kcal / mol and −6.5 Kcal / mol, respectively. The binding energies obtained reflect the in-silico feasibility of forming the RdRp-EGCG-Zn2+ complexes protein com...

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Abstract

EGCG-Zn2+ molecular complexes exhibit a significantly higher affinity than the EGCG molecule alone or Zn2+ molecule alone for binding to different SARS-CoV-2 molecular targets and show virtually complete antiviral suppressive activity (>99%) against this virus in experimental models of infection. EGCG-Zn2+ complexes have a lower toxicity than EGCG alone in transfected human cells. The combination of EGCG and Zn2+, significantly improved some key pharmacokinetic parameters of EGCG in humans. Thus, these complexes are usable as a new broad-spectrum method for chemoprophylaxis or treatment of viral diseases by using formulations containing a composition of EGCG and Zn2+ or EGCG-Zn2+ complexes in sufficient amount to reach a blood concentration with antiviral effect, minimizing human safety issues.

Description

FIELD OF THE DISCLOSURE[0001]The present invention relates to a broad-spectrum antiviral formulation and method for the pre- and post-exposure prophylaxis and treatment of viral infections with very low toxicity in humans; more particularly, to a formulation and method for the pre- and post-exposure prophylaxis and treatment of an infection caused by emerging enveloped viruses such as SARS-CoV-2.SUMMARY OF THE DISCLOSURE[0002]The present invention provides a method of treatment for an individual; the use of a formulation; and a formulation that has been developed and created taking into consideration the extraordinary ability of epigallocatechin-3-gallato (herein EGCG) to bind Zn2 ions by chelation, spontaneously and efficiently forming coordinated covalent molecular compounds of EGCG-Zn2+ (herein EGCG-Zn2+ complexes) at physiological pH 7.4. The inventors have found that these EGCG-Zn2+ complexes have a significantly higher affinity than the EGCG molecule alone or than Zn2+ alone f...

Claims

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Application Information

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IPC IPC(8): A61K33/30A61K47/54A61P31/14
CPCA61K33/30A61P31/14A61K47/547A61K31/555A61K2300/00
Inventor KOCH, ELARD
Owner MELISA INST GENOMICS & PROTEOMICS RES SPA
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