METHOD AND COMPOSITIONS FOR TREATING, PREVENTING OR LIMITING THE OCCURRENCE OF VIRAL INFECTION

Abstract

Method and pharmaceutical compositions for treating or limiting the occurrence of viral infections by administering a therapeutically effective amount of a pharmaceutical composition that targets the ACE2 active site. The pharmaceutical compositions include those of Formula (I), Formula (II), Formula (III), including Formulas (IIIa) and (IIIb), and the viral infections including but not limited to respiratory viruses and disease conditions and syndromes that are associated with the viral infections.

Claims

1. A method for treating or limit the occurrence of viral infection, said method comprising administering a therapeutically effective amount of a pharmaceutical composition comprising formula (I) ##STR00004## wherein R and R.sub.5 are each independently hydrogen, a hydroxy group, an alkoxy group, a rutinosyl group, and a rhamnosyl group; R.sub.1═OH, R.sub.2═OH, R.sub.3═H, R.sub.4═OH and R.sub.6═OH; and a is a single bond or a double bond; provided that at least one of R and R.sub.5 comprises an electrophilic group chosen from aldehyde, haloalkane, alkene, butyryl, fluorophenol, sulfonamide and fluorophenyl sulfoxide, wherein said viral infection is caused by COVID-19.

2. The method of claim 1, wherein the composition is effective for the treatment of a virus by targeting the Angiotensin Converting Enzyme (ACE2) active site for the treatment, prevention or limiting occurrence of infection.

3. The method of claim 2, wherein the viral invention is caused by COVID-19.

4. A method for treating or limit the occurrence of viral infection, said method comprising administering a therapeutically effective amount of a pharmaceutical composition comprising formula II ##STR00005##

5. The method of claim 4, wherein the composition is effective for the treatment of a virus by targeting the Angiotensin Converting Enzyme (ACE2) active site for the treatment, prevention or limiting occurrence of infection.

6. The method of claim 5, wherein the viral invention is caused by COVID-19.

7. A method for treating or limit the occurrence of viral infection, said method comprising administering a therapeutically effective amount of a pharmaceutical composition comprising formula (III) ##STR00006## wherein R, R.sub.1, R.sub.2, R.sub.4, R.sub.5, and R.sub.6 are a hydroxyl group or chlorine, R.sub.3 is hydrogen; and wherein, at least one of R, R.sub.1, R.sub.2, R.sub.4, R.sub.5, and R.sub.6 is chlorine, and wherein said viral infection is caused by COVID-19.

8. The method of claim 7, wherein the composition is effective for the treatment of a virus by targeting the Angiotensin Converting Enzyme (ACE2) active site for the treatment, prevention or limiting occurrence of infection.

9. The method of claim 8, wherein the viral invention is caused by COVID-19.

10. The method of claim 7, wherein formula 3 is selected from the compounds: ##STR00007##

11. The method of claim 1, wherein the pharmaceutical composition further comprises hesperidin and piperine.

12. A method of limiting the occurrence of, reducing the risk or severity of or treating viral infections comprising administering a composition consisting of therapeutically effective amounts of a pharmaceutical composition comprising myricetin and hesperitin to a patient at risk of or diagnosed with viral infection wherein the composition targets the Angiotensin Converting Enzyme (ACE2) active site for the treatment, prevention or limiting occurrence of the viral infection.

13. The method of claim 12, wherein the viral infection is caused by a coronavirus.

14. The method of claim 13, wherein the coronavirus is COVID-19.

15. The method of claim 12, wherein about 300 to about 700 mg myricetin and about 100 to about 500 mg hesperitin are present in the composition.

16. The method of claim 12, wherein about 450 to about 600 mg myricetin and about 250 to about 400 mg hesperitin are present in the composition.

17. The method of claim 12, wherein about 55 to about 75% weight myricetin and about 30 to about 50% hesperitin based on the total weight of the mixture, is present in the composition.

18. The method of claim 12, wherein the ratio of myricetin to hesperitin present in the composition is about (30-60):(30-60).

Description

BRIEF DESCRIPTION OF THE FIGURE

[0027] The sole FIGURE is Table 1 for Δ G (kcal/mol) values for binding of select compounds to the ACE2 active site.

DETAILED DESCRIPTION

[0028] The present invention will now be described with reference to specific examples of treatment using the pharmaceutical compositions of the present invention including administering a therapeutically effective amount of the selected compound.

[0029] As used herein, the following terms and phrases shall have the meaning set forth below.

[0030] The phrase “naturally occurring” when referring to a compound means a compound that is in a form in which it can be found naturally. A compound is not in a form that is naturally occurring if, for example, the compound has been purified and separated from at least some of the other molecules that are found with the compound in nature. A “naturally occurring compound” refers to a compound that can be found in nature, i.e., a compound that has not been created or modified by man.

[0031] “Treating” a condition or disease refers to curing as well as ameliorating at least one symptom of the condition or disease.

[0032] The term “therapeutic effect” is art-recognized and refers to a local or systemic effect in animals, particularly mammals, and more particularly humans caused by a pharmacologically active substance. The phrase “therapeutically effective amount” means that amount of such a substance that produces some desired local or systemic effect at a reasonable benefit/risk ratio applicable to any treatment. The therapeutically effective amount of such substance will vary depending upon the patient and disease or condition being treated, the weight and age of the patient, the severity of the disease or condition, the manner of administration and the like, which can readily be determined by one or ordinary skill in the art. For example, certain compositions described herein may be administered in a sufficient amount to produce a desired effect at a reasonable benefit/risk ratio applicable to such treatment.

[0033] For example, in the context of the therapeutic methods provided in this disclosure, a therapeutically effective amount is an amount that will target the Angiotensin Converting Enzyme (ACE2) active site for the treatment, prevention or limiting occurrence of infection including but not limited to viral infects caused by coronavirus including COVID-19.

[0034] The term “pharmaceutically acceptable carrier” means a carrier or diluent that does not give a stimulus to an organism and destroy the natures and bioactivities of an administered compound.

[0035] The present method and compositions were identified through research and experimentation to determine compounds which target, i.e., bind or act as an inhibitor bound to human Angiotensin Converting Enzyme-related carboxypeptidas (ACE2). Predictive and empirical A G values for binding compounds to the ACE2 active site demonstrated efficacy of the present compounds to treat and limit viral infections. The Δ G values were measured in terms of kcal/mol noting that the more negative the Δ G value, the higher predictive binding affinity. Table 1 (FIGURE) summarizes Δ G values for select compounds effective for treating viral infections in accordance with the disclosed treatment of viral infections.

[0036] The data summarized in Table 1 demonstrates that hesperidin, chlorinated myricetin (compound formula 3(a)), and myricetin are effective in treating viral diseases as targeting the ACE2 binding site. Additional inhibitors of ACE2, i.e., targeting the ACE2 binding site can be identified by conducting similar studies and determining the Δ G value as summarized in Table 1 above and in Table 2 below.

TABLE-US-00001 TABLE 2 Formula α-Pinene Hesperetin Linalool IIIa* Myricetin Blind Docking −6.2 −6.2 −5.9 −7.9 −7.3 −5.9 −5.9 −5.8 −7.9 −7.3 −5.7 −5.7 −5.7 −7.8 −7.3 −5.7 −5.7 −5.6 −7.7 −7.3 −5.7 −5.7 −5.5 −7.7 −7.2 −5.6 −5.6 −5.4 −7.7 −7.2 −5.6 −5.6 −5.3 −7.7 −7.2 −5.5 −5.5 −5.2 −7.5 −7.2 −5.5 −5.5 −5.2 −7.5 −7.2 MERS Pocket Docking −5.9 −6.8 −5.3 −6.6 −6.5 −5.6 −6.4 −5.2 −6.3 −6.2 −5.6 −5.6 −5.1 −5.9 −6.1 −5.5 −5.3 −5.1 −5.8 −5.7

[0037] It will now be clear to a person of ordinary skill in the art that the present compounds are effective for treating various viral infections by acting as ACE2 inhibitors binding to the ACE2 active site. Additional compounds relating to the disclosed compounds a pharmaceutical compositions disclosed here can be used and easily adapted for treating viral infections by identifying those compounds which have affinity for the ACE2 active site.

[0038] Although the invention has been described above in relation to preferred embodiments thereof, it will be understood by those skilled in the art that variations and modifications can be accomplished in these preferred embodiments without departing from the scope and spirit of the invention.