• aldosterone synthase inhibitors

    Aldosterone synthase inhibitor is a highly anticipated drug in cardio-metabolic therapy. We develop compounds that selectively inhibit synthesis of aldosterone for future use in therapy of drug-resistant arterial hypertension and non-genomiс effects of high aldosterone. We are the first to fulfill this gap by solving the crystal structure of aldosterone synthase in complex with substrate and inhibitor.

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  • novel anti-tuberculosis drug

    We’ve identified and validated a new targets – mycobacterial cytochromes P450, responsible for cell wall formation and depression of local immune response in human. This achievement is a basis for a drug discovery for treatment of resistant (MDR, XDR) forms of tuberculosis. 

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  • pipeline potential

    Cancer, infections, inflammation, chronic kidney disease are the examples of pipeline extension potential. 

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aldosterone synthase inhibitors

Development of selective compounds that exclusively inhibit aldosterone synthesis for use in therapy of cardio-metabolic disorders, caused by hyperaldosteronism. Currently there is no drug on the market targeting selectively on aldosterone synthase.

According to the latest WHO data, more than 7.5 million deaths worldwide are caused by high blood pressure (hypertension), representing approximately 12.8% of total deaths. The sum of years lost due to the premature death and disability (indicator DALYs) due to hypertension is 58 million. Special attention is given to resistant forms of hypertension (RFH), when the combination of three or more antihypertensive drugs of different classes cannot eliminate the symptoms of hypertension. Patients with RFH constitute 5-30% of patients with hypertension and have more severe symptoms. 

To a large extent the progression of RFH is related to the excessive aldosterone synthesis (basic human mineralocorticoid hormone). Aldosterone excess is implicated in the development and progression of several different cardiovascular/renal disease processes, including hypertension, congestive heart failure, chronic kidney disease, coronary artery disease and stroke. High aldosterone concentrations have also been associated with insulin resistance and pancreatic ?-cell dysfunction. Most prominent approach to inhibiting aldosterone-induced cardiovascular injury is to suppress its synthesis (i.e., the inhibition of aldosterone synthase). This strategy prevents the non-genomic actions of aldosterone that are not antagonized by MR blockade. Therefore aldosterone synthase (CYP11B2 or AS) has received growing attention as an attractive therapeutic target for antihypertensive drug discovery.

However, the development of selective and potent CYP11B2 inhibitors is particularly challenging due to high homology to the CYP11B1 isoform (93% amino acid sequence identity with CYP11B2) and other steroidogenic enzymes, especially in the absence of structural information. The progress in AS research was hampered for a long time by the inability to obtain a purified protein due to its low stability and membrane nature and as a result no adequate screening systems available.

CRISTA plarform enabled to identify four different scaffolds with strong inhibitory effect on aldosterone synthase — these compounds will be used for molecular docking using the crystal structure of the complex with fadrazole and for subsequent optimization. 

Our compound will have a high inhibitory activity on a specific target (aldosterone synthase), have a minimal inhibitory effect on other enzymes of the steroid hormones biosynthesis and xenobiotic metabolism, and also have low toxicity. 

novel anti-tuberculosis drug

Key facts from WHO:

  • Tuberculosis (TB) is one of the top 10 causes of death worldwide.
  • In 2015, 10.4 million people fell ill with TB and 1.8 million died from the disease (including 0.4 million among people with HIV). Over 95% of TB deaths occur in low- and middle-income countries.
  • In 2015, an estimated 1 million children became ill with TB and 170 000 children died of TB (excluding children with HIV).
  • TB is a leading killer of HIV-positive people: in 2015, 35% of HIV deaths were due to TB.
  • Globally in 2015, an estimated 480 000 people developed multidrug-resistant TB (MDR-TB).  In some cases, more severe drug resistance can develop. Extensively drug-resistant TB (XDR-TB) is a more serious form of MDR-TB caused by bacteria that do not respond to the most effective second-line anti-TB drugs, often leaving patients without any further treatment options. Worldwide, only 52% of MDR-TB patients and 28% of XDR-TB are currently successfully treated. The cost to treat a single XDR-TB case is over €160 000.
The MDR-TB burden largely falls on 3 countries – China, India, and the Russian Federation – which together account for nearly half of the global cases. About 9.5% of MDR-TB cases had XDR-TB in 2015.
“You’re really looking at a global issue .. It’s not a foreign problem, you can’t keep these TB patients out. It’s time people realize that.”
Dr Lee Reichman  (Mendoza, M, “First U.S. case of extremely drug resistant strain of tuberculosis diagnosed”, Associated Press 2009 )

New effective drugs need to be developed to treat of drug resistant (MDR, XDR) forms of tuberculosis. We’ve identified and validates a new targets – mycobacterial cytochromes P450, responsible for cell wall formation and depress of local immune response in human. Our team is developing an effective approach to inhibit a panel of mycobacterial cytochrome P450s with a minimal effect on human enzymes.

New generation of TB-drugs (inhibitors of mycobacterial-P450s) will inhibit the formation of cell wall components (stop growth of mycobacteria and make them sensitive to available dugs), and decrease effects of mycobacterial enzymes on immune system of host organism (increase innate immunoresponse to M.tuberculosis).

pipeline potential

Our unique technological platform allows a substantial pipeline extension to following indications:

  • hormone dependent cancers — best-in-class drugs.
  • infections (fungal, mycobacterial) — first-in-class drugs.
  • chronic kidney disease — first-in-class drug.
  • anti-inflammatory — first-in-class drug.
  • anti-thrombotic — best-in-class drug.