DESC:DESCRIPTION:
Field of the invention:
[0001] The present disclosure generally relates to the technical field of compositions for treatment of gastric ulcers/ gastritis, and in specific relates to a molecule composition based on proteolysis targeting chimera technology for effective treatment of gastritis and gastric ulcers.
Background of the invention:
[0002] Helicobacter pylori (H. pylori) is a gram-negative bacterium that can infect the stomach as early as childhood and cause chronic gastritis for the rest of one's life. The majority of individuals infected with H. pylori do not develop symptoms or diseases. However, only a small percentage of infected people develop symptoms or disease. It is currently difficult to anticipate who could become infected and who stays unaffected due to H. pylori. The bacterium is extremely widespread, infecting more than half of the world's population. In affluent countries, the infection's prevalence rises with age. The infection is seen in 40-60% of people over the age of 50, but less frequently in younger age groups.

[0003] Chronic H. pylori gastritis causes peptic ulcer disease, gastric cancer, and gastric lymphoma. This serious and transmissible infectious disease carries a high morbidity and mortality rate (due to ulcer complications and cancer) and has a great economic impact. Peptic ulcer disease is common and causes a significant economic burden in developed countries, with major spending on acid suppressant drugs. Eradicating H. pylori infection also cures ulcer disease and, since re-infection in adults is extremely rare, adequate treatment permanently prevents chronic disease, including ulcer perforation or bleeding.

[0004] The use of H. pylori medication is becoming more common, and the indications for treatment are growing. Antibiotic therapy is required in all patients with a confirmed peptic ulcer, in those with gastric MALT-lymphoma, in first degree relatives of gastric cancer patients and in patients with atrophic gastritis. Anti-Helicobacter treatment has recently been shown to be effective in individuals with functional dyspepsia, reflux illness, and those who require long-term profound acid suppression. Large-scale studies have also shown that testing any new and previously un-investigated young dyspeptic patients with a non-invasive Helicobacter test is cost-effective. Following a positive result, empirical H. pylori medication would be administered. This so-called "test and treat" technique is becoming more common, and the usage of Helicobacter therapy will expand as this approach is more widely adopted and accepted in primary care.

[0005] In spite of the availability of several therapeutic options H. pylori still poses a challenge to mankind. The existing remedies are not effective against H. pylori. The most commonly used solutions for the problem are antacids (proton pump inhibitors) and antibiotics. However, antacids provide temporary relief and antibiotics fail due to drug resistance. Further, reversible inhibitors may encounter the problem of decreased binding affinity in some cases resulting in therapeutic failure.

[0006] Therefore, there is a need for a composition that aids to effectively cure gastric ulcers/ gastritis caused by Helicobacter pylori. There is also a need for a composition that targets the host-pathogen interaction and provides a solution to H. pylori. There is also a need for a composition that prevents cellular damage to the host. Further, there is a need to develop a thermally stable composition in the form of a small molecule drug.
Objectives of the invention:
[0007] The primary objective of the invention is to develop a composition that aids to solve the problem of gastric ulcers/ gastritis caused due to a bacterium called Helicobacter pylori effectively.

[0008] Another objective of the invention is to develop a composition that targets the host-pathogen interaction and provides a solution to H. pylori.

[0009] The other objective of the invention is to develop a composition that permanently degrades bacterial Cag A to prevent cellular damage to the host cell of the patient.

[0010] Further objective of the invention is to develop a thermally stable composition that can be delivered to patients orally as tablet and/or as an intravenous injection.

[0011] Another objective of the invention is to develop a composition that triggers the cellular inherent ubiquitin-proteasome system (UPS) against the virulent factor (Cag A) of H. pylori.

[0012] Another objective of the invention is to develop a composition that provides permanent relief and does not increase drug resistance in the patient.

[0013] Yet another objective of the invention is to provide a composition that can be easily stored and transported in various forms such as tablets and intravenous injections thereof.

[0014] Another objective of the invention is to develop a composition in the form of a small molecule drug.
Summary of the invention:
[0015] The present disclosure proposes a proteolysis targeting chimera based composition for gastritis and gastric ulcers. The following presents a simplified summary in order to provide a basic understanding of some aspects of the claimed subject matter. This summary is not an extensive overview. It is not intended to identify key/critical elements or to delineate the scope of the claimed subject matter. Its sole purpose is to present some concepts in a simplified form as a prelude to the more detailed description that is presented later.

[0016] In order to overcome the above deficiencies of the prior art, the present disclosure is to solve the technical problem to provide a small molecule composition based on proteolysis targeting chimera for effective treatment of gastritis and gastric ulcers.

[0017] According to an aspect, the invention provides a proteolysis targeting chimera based composition for gastritis and gastric ulcers. The proposed composition permanently degrades the bacterial Cag A thereby preventing further cellular damage to the host cells of the patient. The proposed composition directly targets the host-pathogen interaction between the bacteria and the host cell of the patient. The proposed composition aids to cure gastritis and gastric ulcers caused by Helicobacter pylori (H. pylori) in patients.

[0018] In specific, the small molecule of the proposed composition triggers the cellular inherent ubiquitin-proteasome system (UPS) against the virulent factor (Cag A) of H. pylori such that the bacterial Cag A is permanently degraded. The composition thus prevents further cellular damage to the host. The proteolysis targeting chimera-based composition is suitable to be administered as a thermally stable small molecule in various forms such as tablets and intravenous injections thereof.

[0019] Further, objects and advantages of the present invention will be apparent from a study of the following portion of the specification, the claims, and the attached drawings.
Brief description of drawings:
[0020] The accompanying drawings, which are incorporated in and constitute a part of the specification, illustrate an embodiment of the invention, and, together with the description, explain the principles of the invention.

[0021] FIG. 1 illustrates a flowchart of a process for synthesizing a proteolysis targeting chimera based composition, in accordance to an example embodiment of the invention.

[0022] FIG. 2 illustrates an example graph represents the mass of the proteolysis targeting chimera based composition using a mass spectrometry, in accordance to an example embodiment of the invention.

[0023] FIG. 3 illustrates an example view of a bacterial agar plates in presence of clarithromycin cleared the growth of bacteria, in accordance to an example embodiment of the invention.

[0024] FIG. 4 illustrates an example experimental results of the proteolysis targeting chimera based composition to prevent gastric ulcers, in accordance to an example embodiment of the invention.
Detailed invention disclosure:
[0025] Various embodiments of the present invention will be described in reference to the accompanying drawings. Wherever possible, same or similar reference numerals are used in the drawings and the description to refer to the same or like parts or steps.

[0026] The present disclosure has been made with a view towards solving the problem with the prior art described above, and it is an object of the present invention to provide a small molecule composition based on proteolysis targeting chimera for effective treatment of gastritis and gastric ulcers.

[0027] According to an exemplary embodiment of the invention, a proteolysis targeting chimera (PROTAC) based composition for gastritis and gastric ulcers is disclosed. The proposed composition directly targets the host-pathogen interaction between the bacteria and the host cell of the patient. In specific, the small molecule of the proposed composition triggers the cellular inherent ubiquitin-proteasome system (UPS) against the virulent factor (Cag A) of H. pylori such that the bacterial Cag A is permanently degraded. The proposed composition permanently degrades the bacterial Cag A, thereby preventing further cellular damage to the host cells of the patient.

[0028] The proposed composition aids to cure gastritis and gastric ulcers caused by Helicobacter pylori (H. pylori) in patients. The composition thus prevents further cellular damage to the host. The proteolysis targeting chimera (PROTAC) based composition is suitable to be administered as a thermally stable small molecule in various forms such as tablets and intravenous injections thereof. Unlike antacids and antibiotics, the present composition provides permanent relief and does not increase drug resistance in the patient.

[0029] Conventional methods such as antibiotics and antacids increase drug resistance in the patient whereas reversible inhibitors may encounter reduced binding affinity which further causes therapeutic failure. However, the binding affinity and drug resistance in patient do not affect the proposed composition while curing gastritis or gastric ulcers. The proposed composition is subject to in-vitro evaluation along with ADME-Tox profiling.

[0030] According to another exemplary embodiment of the invention, FIG. 1 refers to an example flowchart 100 of a process for synthesizing a proteolysis targeting chimera (PROTAC) based composition. At step 102, the compound benzene-1 2 4-tricarboxylic acid is used to synthesize the compound benzene- 1,2, 4-tricarbonyl trichloride in the presence of thionyl chloride as shown in the figure below

[0031] At step 104, an amine compound is synthesized using a reductive amination mechanism to convert pyrrolidin-4-one and pyrrolidine to form 4-(pyrrolidin-1-yl)piperidine. The reaction is shown in the below figure:

[0032] At step 106, the synthesized compounds benzene- 1,2, 4-tricarbonyl trichloride and the 4-(pyrrolidin-1-yl)piperidine are reacted to form a a core compound of the helicobacter targeting chimera composition (HelicoTAC) in the presence of triethylamine (Et3N) by a amide coupling method. The reaction as shown in the figure below:

[0033] At step 108, the core compound of the helicobacter targeting chimera is coupled with the plurality of compounds of the proteolysis targeting chimera (PROTAC) to synthesize the helicobacter targeting chimera composition (HelicoTAC). Herein one embodiment, the plurality of compounds of the proteolysis targeting chimera (PROTAC) versions comprises of MA01056, MA01058, MA01059 and MA01060 series containing either Pyrazinamide (PZA) or Pyrazinoic acid (POA).

[0034] The PROTAC versions of MA01056, MA01058, MA01059, and MA01060 are shown in the figures bellow:

[0035] Herein one embodiment, the plurality of the compounds in the proteolysis targeting chimera (PROTAC) versions containing a pyrazinamide (PZA) or a pyrazinoic acid (POA) to couple with the core compound of the helicobacter targeting chimera to synthesise the final helicobacter targeting chimera composition. The helicobacter targeting chimera composition (HelicoTAC) composition is a combination of a core molecule (MA01052). that was identified in this study and the PROTAC versions (MA01056, MA01058, MA01059 and MA01060 series containing either pyrazinamide (PZA) or pyrazinoic acid (POA) that are coupled to the core molecule (MA01052) using various linker molecules) of the same molecule. The helicobacter targeting chimera composition with the core molecule (MA01052) is shown in the figure below:

[0036] In an embodiment herein, the helicobacter targeting chimera composition (HelicoTAC) can interact with the cytotoxin associated protein (Cag A) when it is in a general antibiotic nature and the virulence protein of the Helicobacter pylori is reversible, thereby temporary inhibiting gastric ulcers. The PROTAC version of HelicoTAC will permanently degrade the Cag A protein of H. pylori by leveraging the bacterial and/or host cell proteasome system thus providing a prolonged relief from the gastric ulcers. Herein one embodiment, the relief from the gastric ulcers is provided by disabling the H. pylori bacterial infection but not by directly acting on the gastric cells of the host.

[0037] Herein one embodiment, the proteolysis targeting chimera (PROTAC) versions of the novel core molecule (MA01052) depend on the bacterial proteasome activation by the PZA/POA moiety of our compounds for the degradation of the bacterial cytotoxin associated protein (Cag A) protein. An alternate version of this is core molecule (MA01052) linked to the thalidomide or pomalidomide as the E3 Ligase ligands in order to target the cytotoxin associated protein (Cag A) to the host cell ubiquitin-proteasome system.

[0038] In an embodiment herein, the moieties such as thalidomide/pomalidomide can be replace the Pyrazinamide (PZA) or the Pyrazinoic acid (POA) moieties. The final composition of the helicobacter targeting chimera composition (HelicoTAC) can be a combination of the parent molecule of the core molecule (MA01052) and one or two versions of it’s the proteolysis targeting chimera (PROTAC) containing the the Pyrazinamide (PZA) or the Pyrazinoic acid (POA) ligand and the thalidomide or the pomalidomide ligand.

[0039] According to another exemplary embodiment of the invention, FIG. 2 refers to an example graph 200 represents the mass of the proteolysis targeting chimera (PROTAC) based composition using a mass spectrometry. The final compound helicobacter targeting chimera composition (HelicoTAC) is analyzed with mass spectrometry to confirm its mass. The mass spectrum is shown in FIG. 2.

[0040] According to another exemplary embodiment of the invention, FIG. 3 refers to an example view of a bacterial agar plates 300 in presence of clarithromycin cleared the growth of bacteria. For instance, the toxicology analysis and then further the helicobacter targeting chimera composition (HelicoTAC) to clinical trials. The in vitro antibacterial activity studies using bacterial agar plates 300 as shown in FIG. 3. The presence of clarithromycin (used as a positive control in this study) cleared the growth of bacteria. It is evident that the minimum concentration of clarithromycin that is required to clear the bacterial growth is 10 µg/ml. further, increase in clarithromycin concentrations beyond 10 ug/ml large clearance zones can be seen on the bacterial agar plates 300.

[0041] According to another exemplary embodiment of the invention, FIG. 4 refers to an example experimental results 400 of the proteolysis targeting chimera (PROTAC) based composition to prevent gastric ulcers. For instance, based on this positive control, the lead compound of the core molecule (MA01052) is evaluated at two concentrations initially for 7 ug/ml and 14 ug/ml. As shown in FIG. 4, both concentrations such as 7 ug/ml and 14 ug/ml shows bacterial growth suggesting that higher concentrations of the core molecule (MA01052) are needed for better inhibition of bacterial growth. However, the core molecule (MA01052) has some inhibitory activity compared to the positive control plate shown below.

[0042] For instance in FIG. 4, the sample 404 represents the negative control, where no bacteria is plated whereas the sample 404 represents positive control where the bacteria is plated without the core molecule (MA01052). Further, the sample 406 and 408 represents the back and front views of the plate with 7 ug/ml concentration respectively. The sample 412 and 410 represents the back and front views of the plate with 14 ug/ml concentration respectively. The dark colour coloration on the plates is due to the helicobacter targeting chimera composition (HelicoTAC) compound and not due to the bacterial growth.

[0043] Herein one embodiment, the pyrazinamide (PZA) or the pyrazinoic acid (POA) as a part of the helicobacter targeting chimera composition (HelicoTAC). Both the pyrazinamide (PZA) and the Pyrazinoic acid (POA) specifically activate the bacterial proteasomes to degrade bacterial protein within the bacterial cells. For instance, in patent application, the core molecule (MA01052) (parent molecule) that was identified as an antibiotic is linked with either the pyrazinamide (PZA) or the pyrazinoic acid (POA) in order to target the Helicobacter pylori cytotoxin associated protein (Cag A) protein to the bacterial proteasome for degradation. In the same way, the parent molecule can also be linked with thalidomide/pomalidomide to target the cytotoxin associated protein (Cag A) protein to the host cell ubiquitin-proteosome system. Based on our preliminary data we speculate that the helicobacter targeting chimera composition (HelicoTAC), by inhibiting the growth of Helicobacter pylori, can also stop the gastric ulcers from progressing into gastric cancers.

[0044] In an embodiment herein, the molecular docking results strongly suggest that the designed core molecule (MA01052, also known as MA01027) in the PROTAC molecule has anti-microbial activity. The core compound is also expected to show anti-microbial activity not only towards helicobacter pylori but can also shows anti-microbial activity towards other bacteria as well. The cytotoxin associated protein (Cag A) is the bacterial virulence factor that is primarily causing the gastric cancer. Helicobacter targeting chimera composition (HelicoTAC) is expected to have some activity in reducing the severity of cancer helping the cancer patients.

[0045] Herein one embodiment, the helicobacter targeting chimera composition (HelicoTAC) shows anti-microbial activity with a minimal inhibitory concentration >14 µg/ml. The cytotoxin associated protein is proved to play a major role in causing cancer by interacting with the other helicobacter pylori proteins like vacuolization cytotoxin (Vac A) which is also identified to solve up to some extent by evaluating the helicobacter targeting chimera composition (HelicoTAC) towards vacuolization cytotoxin (Vac A). The plurality of compounds of the proteolysis targeting chimera (PROTAC) in acidic conditions increases anti-microbial activity towards the helicobacter pylori degradation. The plurality of compounds of the proteolysis targeting chimera (PROTAC) increasing its efficiency for the anti-microbial activity towards H. pylori as it survives in the acidic pH.

[0046] Numerous advantages of the present disclosure may be apparent from the discussion above. In accordance with the present disclosure, a composition that aids to cure gastric ulcers/ gastritis caused due to a bacterium called Helicobacter pylori effectively is proposed.

[0047] The composition targets the host-pathogen interaction and provides a solution to H. pylori. The proposed small molecule composition permanently degrades bacterial Cag A to prevent cellular damage to the host. Further, the proposed composition can be easily stored and transported. The disclosed composition is a thermally stable composition that can be delivered to patients orally as tablet and/or as an intravenous injection. The proposed composition may be prepared in other forms such as capsules or syrups thereof.

[0048] It will readily be apparent that numerous modifications and alterations can be made to the processes described in the foregoing examples without departing from the principles underlying the invention, and all such modifications and alterations are intended to be embraced by this application.
,CLAIMS:CLAIMS:
I/We Claim:
1. A process for synthesizing a proteolysis targeting chimera based composition, comprising:
synthesizing benzene- 1,2, 4-tricarbonyl trichloride using a compound of benzene-1 2 4-tricarboxylic acid in the presence of thionyl chloride;

converting pyrrolidin-4-one and pyrrolidine by a reductive amination mechanism to synthesize 4-(pyrrolidin-1-yl)piperidine;

coupling, the synthesized compounds benzene- 1,2, 4-tricarbonyl trichloride and the 4-(pyrrolidin-1-yl)piperidine to form a core compound of the helicobacter targeting chimera in the presence of triethylamine (Et3N) by a amide coupling method; and

coupling the core compound of the helicobacter targeting chimera with the plurality of compounds of the proteolysis targeting chimera to synthesize the helicobacter targeting chimera.
2. The process as claimed in claim 1, wherein the plurality of compounds of the proteolysis targeting chimera comprises:

3. The process as claimed in claim 1, wherein the plurality of compounds containing a pyrazinamide (PZA) or a pyrazinoic acid (POA) to couple with the core compound of the helicobacter targeting chimera to synthesise the final helicobacter targeting chimera composition.
4. The process as claimed in claim 1, wherein the core compound of the helicobacter targeting chimera coupled to thalidomide or pomalidomide as E3 Ligase ligands in order to target a cytotoxin associated protein (Cag A) to the host cell ubiquitin-proteasome system.
5. The process as claimed in claim 1, wherein the final helicobacter targeting chimera composition triggers the cellular inherent ubiquitin-proteasome system (UPS) against a virulent protein of a Helicobacter pylori to degrade the cytotoxin associated protein (Cag A) permanently to provide relief from the gastric ulcers.
6. The process as claimed in claim 1, wherein the plurality of compounds of the proteolysis targeting chimera in acidic conditions increases anti-microbial activity towards Helicobacter pylori degradation.
7. The process as claimed in claim 1, wherein the final helicobacter targeting chimera composition having anti-microbial activity with a minimal inhibitory concentration of greater than 14 µg/ml.