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A Mitochondrial Uncoupler for NASH Treatment

Widely Distributed in Liver Without Mitochondrial Toxicity

Home / Available Projects / A Mitochondrial Uncoupler for NASH Treatment

  • Overview
  • Target
  • Drug Modality
  • Indication
  • Mechanism of Action
  • Status
  • Data
Drug Name MB-X01Y03

Mitochondria are at the center of cellular metabolism. Alteration in mitochondrial function causally contributes to many diseases. It has long been proposed that these diseases could be effectively treated by modulating or correcting mitochondrial function.

MB-X01Y03 is a new mitochondrial uncoupler developed to treat non-alcoholic steatohepatitis (NASH). Unlike the traditional small-molecule mitochondrial uncouplers, the distribution of MB-X01Y03 is greatly enhanced in the liver and the mitochondrial toxicity is eliminated. MB-X01Y03 can improve all pathological symptoms of NASH, including steatosis, insulin resistance, fibrosis, and liver damage.

The IND application will soon be submitted.

Target Mitochondria
Drug Modality Small molecule
Indication Non-alcoholic steatohepatitis (NASH)
Product Category Mitochondrial uncoupling agent
Mechanism of Action MB-X01Y03 was developed to dissipate abnormal liver lipid accumulation by modulating mitochondrial function via safely uncoupling mitochondrial respiration.
Status IND
Patent Granted

Collaboration Opportunity

Protheragen Inc. is actively seeking partnership for MB-X01Y03. Potential collaboration can be strategic alliance, licensing, or marketing agreement.

We look forward to hearing from you.


Mitochondria are cell organelles where respiration occurs. They contain two compartments bounded by inner and outer membranes. The outer membrane is permeable to small metabolites, whereas the permeability of the inner membrane is controlled to maintain the high electrochemical gradient created by the mitochondrial respiratory chain that is necessary for energy conservation and ATP synthesis in mitochondria.

Mitochondrial uncoupling is a process that decouples mitochondrial oxidation from ATP synthesis, naturally induced by mitochondrial uncoupler proteins (UCPs). Small-molecule mitochondrial uncouplers, which mimic the physiological effects and functions of UCP1 and UCP2/3, similarly induce mitochondrial uncoupling for burning excess fat calories, consuming cellular metabolites otherwise used for cell proliferation, and cell protection against oxidative stress.

Figure. From Cells. 2019 Aug; 8(8): 795.

Small Molecule

MB-X01Y03 is a new small molecule mitochondrial uncoupler that can enrich liver distribution and eliminate mitochondrial toxicity. Different from the conventional mitochondrial uncoupler, MB-X01Y03 is highly efficacious in dissipating excess fat in humans and has a wide therapeutic index.

Non-alcoholic Steatohepatitis (NASH)

Nonalcoholic fatty liver disease (NAFLD) is a continuum of liver conditions, with two major subtypes: nonalcoholic fatty liver is also termed simple steatosis, which is the nonprogressive form and seldom evolves to cirrhosis; nonalcoholic steatohepatitis (NASH) is a disease that in addition to fat accumulation in the liver, it is also characterized by the presence of inflammation and hepatocyte injury.

The accumulation of free fatty acids and increase in triglyceride levels in patients with NAFLD are associated with the production of free radicals, leading to lipid peroxidation and activation of proinflammatory and fibrogenic cytokines. The resulting combination of lipid accumulation and inflammation in the liver leads to the transformation of hepatic steatosis to NASH. Fibrosis is reported in 37% to 84% of patients with NASH, and is associated with activation of hepatic stellate cells by proinflammatory factors and growth factors. NASH accompanied by fibrosis progresses faster than NASH without fibrosis.

In a meta-analysis of studies published from 1989 to 2015, the pooled overall global prevalence of imaging-diagnosed NAFLD was found to be 25.24%. Among the global population of patients with diagnosed NAFLD, the overall pooled prevalence of biopsy-diagnosed NASH was 59.1%. In the same period, the annual incidence of hepatocellular carcinoma in patients with NASH was 5.29 per 1,000 person-years. For patients with NASH, pharmacotherapeutic options should be reserved. The goal of NASH treatment is the prevention of cardiovascular disease, liver decompensation and progression to hepatocellular carcinoma.

Dissipating Abnormal Liver Lipid Accumulation by Modulating Mitochondrial Function

Excess fat accumulation is a key root cause of NASH. Mitochondria are the major sites for lipid oxidation in cells. As a lipophilic weak acid functioning within the mitochondrial inner membrane, MB-X01Y03 mimics the physiological effects and functions of mitochondrial uncoupler proteins. Near the outer membrane where proton concentration is high, MB-X01Y03 is protonated. Through random movement, the protonated MB-X01Y03 move to the matrix side, where they are deprotonated. The protons are then released to the mitochondrial matrix, where the proton concentration is low. As a result, the energy derived from oxidation of fat is directly converted to heat rather than for ATP synthesis.

MB-X01Y03 was shown to impact steatosis and fibrosis, such as dissipating hepatic fat accumulation, sensitizing hepatic insulin resistance, reducing liver damage, preventing and reversing inflammation, and inhibiting hepatic stellate cell activation.

The Status of MB-X01Y03

Pharmacodynamics, toxicology, and pharmacokinetics tests in vivo have been completed. The IND application will soon be submitted.

Efficacy of MB-X01Y03 in HFD Mouse Model

In high fat diet (HFD) mouse model, MB-X01Y03 (Y03) reduced blood glucose, insulin resistance, steatosis, plasma triglyceride and non-HDL cholesterol (not shown in the figure).

Efficacy of MB-X01Y03 in CCl4 Mouse Model

Comparing to the control group, MB-X01Y03 (Y03) reduced hepatic inflammation and fibrosis in mice with carbon tetrachloride (CCl4)-induced liver fibrosis.

Protheragen’s business is growing rapidly after founded in Ronkonkoma, New York. More offices have been established at different locations across China and the US ever since.

Protheragen Inc.