FIELD OF THE INVENTION

The disclosure provides a method of using triterpenoids for treating coronavirus infection. In particular, the method includes using maslinic and oleanolic acids triterpenoids derivatives in SARS-CoV-2 infection treatment. The antiviral property of the derivative compounds is based on their ability to impair the viral replication of SARS-CoV-2 by disturbing a viral function of SARS-CoV-2 main protease.

BACKGROUND

Coronaviruses (CoVs) are positive single-stranded (+ss) RNA viruses that are classified within the family Coronaviridae. The infectious bronchitis virus (IBV) was the first-discovered CoV that caused an outbreak of respiratory illness in chickens in the 1930s. Reports on mouse hepatitis virus (MHV) and transmissible gastroenteritis virus (TGEV) that infected mice and pigs, respectively, followed in the 1940s. In humans, HCoV-229E and HCoV-OC43, were identified in the 1960s as the causative agents of mild respiratory diseases that present as common cold. Since then, five other HCoVs were identified at different times, including Severe Acute Respiratory Syndrome-CoV (SARS-CoV) in 2003, HCoV-NL63 in 2004, HCoV-HKU1 in 2005, Middle East Respiratory Syndrome-CoV (MERS-CoV) in 2012, and the most recently discovered Severe Acute Respiratory Syndrome-CoV-2 (SARS-CoV-2) in December 2019.

Since its emergence, SARS-CoV-2 infection subsequently expanded to all over the world in a very short period of time. To date, 160 million people have been infected with mortality and morbidity still rising in various parts of the world. As a result, there has been a thrust towards rapid development of vaccines and anti-rival drugs against SARS-CoV-2 to combat the rapidly spreading of the viral infection as well as to provide effective treatment options for patients. Several antiviral-drugs have been approved by the FDA for their uses in SARS-CoV-2 patient treatments [1-3]. In parallel, several clinical trials to virtually recommend or practically test the anti-SARS-CoV-2 activity of synthetic compounds, natural extracts and immunomodulatory agents have been attempted [4-7].

Triterpenes are a class of natural molecules made up of 30 carbon atoms. There are about 200 different skeletons known to date, which are isolated from natural sources of the cyclization of (3S)-2,3-epoxy-2,3-dihydrosqualene and sometimes from squalene itself. These molecules are in most cases hydroxylated at C-3 position due to the opening of the epoxide during cyclization [8]. In the plant kingdom, terpenoids are secondary metabolites, whose ecological role has been proven, especially in the process of communications and defense. Triterpenes, of which more than 30,000 structures are previously isolated and characterized, are derived from natural sources or enzymatic reactions. Additionally, they comprise 47 sub-classes with enormous chemical diversity [8-11]. Triterpenes are among the natural substances with promising biological, therapeutic, and industrial value. In recent years, due to the broad spectrum of their biological potentials, triterpenes have been the subject of an intensive number of research works, which mainly have focused on their biopharmaceutical development. Indeed, triterpenes and their structural analogues display various biological effects such as hemolytic, hypocholesterolimic, immunostimulant, anti-inflammatory, antimicrobial, antiparasitic, cytotoxic, and anti-ulcer [12-18]. Moreover, triterpenes are known for their many important antiviral activities such as anti-hepatitis B virus activity, anti-HIV1 and 2, AIDS, anti-hepatitis C virus activity, and anti-Herpes simplex virus activity (FIG. 1) [11,19].

There is a great need to quickly develop and verify efficacy and safety of therapeutic treatment for viral infection from SARS-CoV-2 as well as its quickly spreading new variants. Further, there is a need for diversifying new SARS-CoV-2 treatment options and more specifically to new targets by using safer therapeutic compounds (e.g., compounds derived from natural sources) in the most cost effective and safety-oriented manner.

SUMMARY OF THE INVENTION

An aspect of the disclosure provides a method of treating coronavirus infection in a subject in need thereof, comprising the step of administering a coronavirus therapeutic composition to the subject in an amount sufficient to treat the infection. In some embodiments, the method includes the step of administering SARS-CoV-2 therapeutic composition comprising at least one triterpenoid selected from the group of triterpenoids 3-17 or combinations thereof. In some embodiments, the triterpenoids 3-17 are oleanolic acid and/or maslinic acid derivatives, wherein the triterpenoid 3 has the chemical structure of Formula III;



wherein the triterpenoid 4 has the chemical structure of Formula IV;



wherein the triterpenoid 5 has the chemical structure of Formula V;



wherein the triterpenoid 6 has the chemical structure of Formula VI;



wherein the triterpenoid 7 has the chemical structure of Formula VII;



wherein the triterpenoid 8 has the chemical structure of Formula VIII;



wherein the triterpenoid 9 has the chemical structure of Formula IX;



wherein the triterpenoid 10 has the chemical structure of Formula X;



wherein the triterpenoid 11 has the chemical structure of Formula XI;



wherein the triterpenoid 12 has the chemical structure of Formula XII;



wherein the triterpenoid 13 has the chemical structure of Formula XIII;



wherein the triterpenoid 14 has the chemical structure of Formula XIV;



wherein the triterpenoid 15 has the chemical structure of Formula XV;



wherein the triterpenoid 16 has the chemical structure of Formula XVI;



wherein the triterpenoid 17 has the chemical structure of Formula XVII.



Another aspect of the disclosure provides a method of inhibiting coronavirus growth, comprising: contacting coronavirus particles with a composition comprising a compound selected from the group consisting of triterpenoids 3-17 or combinations thereof, wherein the compound is used in an amount sufficient to inhibit the coronavirus growth. In some embodiments, the composition comprises a compound that is capable of interacting and forming a hydrogen bond with at least one amino acid of SARS-CoV-2 main protease to suppress anti-viral activities of the SARS-CoV-2 main protease. In some embodiments, the amount sufficient to inhibit the coronavirus growth is a concentration of the compound to partially or completely inhibit a proteolytic activity of SARS-CoV-2 main protease. In some embodiments, the triterpenoids 3-17 are oleanolic acid and/or maslinic acid derivatives,

wherein the triterpenoid 3 has the chemical structure of Formula III;



wherein the triterpenoid 4 has the chemical structure of Formula IV;



wherein the triterpenoid 5 has the chemical structure of Formula V;



wherein the triterpenoid 6 has the chemical structure of Formula VI;



wherein the triterpenoid 7 has the chemical structure of Formula VII;



wherein the triterpenoid 8 has the chemical structure of Formula VIII;



wherein the triterpenoid 9 has the chemical structure of Formula IX;



wherein the triterpenoid 10 has the chemical structure of Formula X;



wherein the triterpenoid 11 has the chemical structure of Formula XI;



wherein the triterpenoid 12 has the chemical structure of Formula XII;



wherein the triterpenoid 13 has the chemical structure of Formula XIII;



wherein the triterpenoid 14 has the chemical structure of Formula XIV;



wherein the triterpenoid 15 has the chemical structure of Formula XV;



wherein the triterpenoid 16 has the chemical structure of Formula XVI;



wherein the triterpenoid 17 has the chemical structure of Formula XVII.



Additional features and advantages of the present invention will be set forth in the description of disclosure that follows, and in part will be apparent from the description of may be learned by practice of the disclosure. The disclosure will be realized and attained by the compositions and methods particularly pointed out in the written description and claims hereof.

