US-12616687-B2 - Treatment of viral infection, disease or disorder using a selective sir agonist

Abstract

The subject invention provides a method for treating, reducing the incidence, suppressing or inhibiting a viral infection, disease, disorder or symptoms thereof in a subject in need thereof comprising administering to the subject a selective S1R agonist. In another aspect, the viral disease is COVID-19, and the selective S1R agonist is pridopidine or pharmaceutically acceptable salt thereof.

Inventors

• Michael Hayden
• Michal Geva

Assignees

• PRILENIA NEUROTHERAPEUTICS LTD.

Dates

Publication Date

20260505

Application Date

20221104

Claims (18)

1. 1 . A method for treating, reducing the incidence, suppressing or inhibiting a viral infection, disease, disorder or symptoms thereof in a subject in need thereof comprising administering to the subject a composition comprising pridopidine or a pharmaceutically acceptable salt thereof, wherein the viral infection, disease, or disorder comprises human coronavirus, SARS, MERS coronavirus, SARS coronavirus 2, or mutations therefrom.
2. 2 . The method of claim 1 , wherein the disease is COVID-19.
3. 3 . The method of claim 1 , wherein the method further reduces ER stress in the subject.
4. 4 . The method of claim 2 , wherein the symptoms of COVID-19 comprise, renal failure, fever, tiredness, dry cough, aches and pains, nasal congestion, runny nose, sore throat, diarrhea or combination thereof.
5. 5 . The method of claim 1 , wherein the composition further comprises at least one of its analog compounds 1-7, or salts thereof:
6. 6 . The method of claim 5 , wherein the method comprises administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof, in combination with compound 1 or pharmaceutically acceptable salt thereof.
7. 7 . The method of claim 5 , wherein the method comprises administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof in combination with compound 1 or pharmaceutically acceptable salt thereof and compound 4 or pharmaceutically acceptable salt thereof.
8. 8 . The method of claim 5 , wherein the pridopidine is in a base form or a pharmaceutically acceptable salt form.
9. 9 . The method of claim 5 wherein the pridopidine salt comprises pridopidine hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, D,L-tartrate, L-tartarate, D-tartarate, pantothenate, bitartrate, ascorbate, succinate, hemisuccinate, maleate, gentisinate, gentisate, fumarate, gluconate, glucaronate, glycolate, saccharate, formate, besylate, benzoate, glutamate, malate, methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate, oxalate, tosylate, naphtalen-2-sulfate, or pamoate salts.
10. 10 . A method of reducing endoplasmic reticulum stress (ER stress) due to a viral infection, disease or disorder in a subject, comprising administering to the subject a composition comprising pridopidine or a pharmaceutically acceptable salt thereof, wherein the viral infection, disease, or disorder comprises human coronavirus, SARS, MERS coronavirus, SARS coronavirus 2, or mutations therefrom.
11. 11 . The method of claim 10 , wherein the disease is COVID-19.
12. 12 . The method of claim 10 , wherein the composition further comprises at least one of its analog compounds 1-7, or salts thereof;
13. 13 . The method of claim 12 , wherein the method comprises administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof in combination with compound 1 or pharmaceutically acceptable salt thereof.
14. 14 . The method of claim 12 , wherein the method comprises administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof in combination with compound 1 or pharmaceutically acceptable salt thereof and compound 4 or pharmaceutically acceptable salt thereof.
15. 15 . The method of claim 12 , wherein the pridopidine is in a base form or a pharmaceutically acceptable salt form.
16. 16 . The method of claim 12 , wherein the pridopidine salt comprises pridopidine hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, D,L-tartrate, L-tartarate, D-tartarate, pantothenate, bitartrate, ascorbate, succinate, hemisuccinate, maleate, gentisinate, gentisate, fumarate, gluconate, glucaronate, glycolate, saccharate, formate, besylate, benzoate, glutamate, malate, methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate, oxalate, tosylate, naphtalen-2-sulfate, or pamoate salts.
17. 17 . The method of claim 1 , wherein the pridopidine salt comprises pridopidine hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, D,L-tartrate, L-tartarate, D-tartarate, pantothenate, bitartrate, ascorbate, succinate, hemisuccinate, maleate, gentisinate, gentisate, fumarate, gluconate, glucaronate, glycolate, saccharate, formate, besylate, benzoate, glutamate, malate, methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate, oxalate, tosylate, naphtalen-2-sulfate, or pamoate salts.
18. 18 . The method of claim 10 , wherein the pridopidine salt comprises pridopidine hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, D,L-tartrate, L-tartarate, D-tartarate, pantothenate, bitartrate, ascorbate, succinate, hemisuccinate, maleate, gentisinate, gentisate, fumarate, gluconate, glucaronate, glycolate, saccharate, formate, besylate, benzoate, glutamate, malate, methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate, oxalate, tosylate, naphtalen-2-sulfate, or pamoate salts.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application is a Continuation-in-Part Application from International Application No. PCT/IL2021/050507 filed 4 May 2021 which claims the benefit of U.S. Ser. No. 63/019,465, filed on 4 May 2020 which are incorporated in their entirety herein by reference. FIELD OF THE INVENTION The subject invention provides a method for treating, reducing the incidence, suppressing or inhibiting a viral infection, disease, disorder or symptoms thereof in a subject in need thereof, comprising administering to the subject a selective S1R agonist. In another aspect, the viral disease is COVID-19, and the selective S1R agonist is pridopidine or a pharmaceutically acceptable salt thereof. BACKGROUND OF THE INVENTION Coronavirus disease 2019 or COVID-19 has rapidly emerged as a global pandemic. As of end of April 2021 there are nearly 150 million confirmed cases and over 3 million deaths in more than 100 countries. There are a small number of treatments which received emergency approval, and vaccinations have only recently become available. Coronaviruses have a single-stranded RNA genome and encode for many similar proteins. Protein and RNA replication machinery are the classic targets for antiviral drugs in development for the past years. However, the lifecycle of coronaviruses relies on several host-cell encoded cellular pathways (Nabirotchkin et al. 2020). Among these pathways are the ER-stress Unfolded Protein Response (UPR), autophagy and Mitochondrial function. A recent bioinformatic/proteomic analysis (Gordon et al. 2020) identified SARS-CoV-2 proteins that interact with the human Sigma-1 and Sigma-2 receptors (S1R/S2R) and contribute to the development of the disease. This highlights sigma receptors as a potential drug target for treating COVID-19. Of the ˜20 viral-encoded proteins, Nsp6 and Or19c were identified as directly interacting with Sigma receptors. The S1R is an ER chaperone protein located at the mitochondrial associated membranes (MAM) that plays a key role in ER-mitochondrial interactions. S1R regulates ER stress, mitochondrial function, calcium signaling, autophagy and cellular homeostasis (Weng, Tsai, and Su 2017; Delprat et al. 2020). S1R deletion enhances ER stress and oxidative stress while S1R overexpression and activation by different agonists restores cellular homeostasis and enhances survival. S1R activation is shown to reduce ER stress, restore mitochondrial function and enhance autophagy (Tesei et al. 2018; Maurice et al. 1994; Christ et al. 2019). The S2R is an intracellular chaperon protein which was recently cloned and identified as TMEM97 (Alon et al. 2017). Although the S1Rs and the S2Rs are not genetically related, they share a similar pharmacological profile and some S1R ligands also show high affinity towards the S2R including haloperidol and DTG, (Longhitano et al. 2017; Tesei et al. 2018; Katnik et al. 2006) Several S2R ligands are shown to induce apoptosis, which makes them attractive anti-cancer drugs (Tesei et al. 2019). Several Sigma ligands were recently reported to show anti-viral activity (Gordon et al. 2020). The Sigma ligands that demonstrated anti-viral activity (measuring viral titer assay) included hydroxychloroquine, Clemastine and Haloperidol. All these compounds show high affinity for the S1R as well as high affinity for the S2R, thus all are non-selective compounds. Ki for S1R vs S2R: hydroxychloroquine is 200 nM and 800 nM respectively, Clemastine S1R Ki is 10 nM vs 20 nM for S2R, and Haloperidol has S1R Ki of 4 nM vs S2R Ki of 54 nM. Gordon in his manuscript presents anti-viral activity with hydroxychloroquine, Clemastine and Haloperidol (Gordon et al. 2020). Hydroxychloroquine anti-viral activity demonstrated at ˜2 uM which was associated with ˜30% reduction in cell viability (Gordon et al. 2020). The effective Clemastine dose for anti-viral activity is 10 uM, and this dose is also associated with ˜40% cell death. Similarly, Haloperidol's anti-viral effect was demonstrated at 100 uM, with ˜30% cell death (Gordon et al. 2020). Pridopidine (4-[3-(methylsulfonyl)phenyl]-1-propyl-piperidine) is a highly selective S1R ligand with Ki=0.57 nM and S2R Ki of 5450 nM (Johnston et al. 2019). Thus, pridopidine has 95-fold higher affinity for the S1R vs the S2R and is the most selective S1R ligand. SUMMARY OF THE INVENTION In the first aspect, the invention provides a method for treating, reducing the incidence, suppressing or inhibiting a viral infection, disease, disorder or symptoms thereof in a subject in need thereof comprising administering to the subject a composition comprising a selective S1R agonist. In a further aspect the invention provides a method of reducing endoplasmic reticulum stress (ER stress) due to a viral infection, disease or disorder in a subject, comprising administering to the subject a composition comprising a selective S1R agonist. In a further aspect the invention provides a method for treating, reducing the