projects
  • aldosterone synthase inhibitor

    Aldosterone synthase inhibitor is a highly anticipated drug in cardio-metabolic indication. Future drug will selectively inhibit synthesis of aldosterone .

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  • anti-TB drug

    Wу are targeting a mycobacterial cytochromes P450, responsible for cell wall formation and depression of local immune response in human., for treatment of resistant (MDR, XDR) forms of tuberculosis. 

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  • pipeline potential

    Separate progect serving to improve our technological platform, combined with pipeline extension and scientific collaborations activities

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aldosterone synthase inhibitor

The mineralocorticoid hormone aldosterone is an important regulator of blood pressure and electrolyte balance. However, excess aldosterone can be deleterious as a driver of processes, that lead to maladaptive cardiovascular and renal remodeling inflammation, insulin resistance, tissue fibrosis endothelial dysfunction, glomerular hyperfiltration, and excess glomerular and tubular leakage of albumin, associated with cardiometabolic disorders such as resistant arterial hypertension, chronic heart failure, chronic kidney disease and diabetic nephropathy. Mineralocorticoid receptor antagonists (MRA) and renin-angiotensin-aldosterone system (RAAS) antagonists are current clinical therapies used to antagonize deleterious effects of aldosterone in patients. MRAs compete with aldosterone for binding at its cognate receptor thereby limiting its effect while RAAS antagonists reduce aldosterone levels indirectly by blocking the stimulatory effect of angiotensin. Both MRAs and RAAS antagonists can result in incomplete inhibition of the harmful effects of excess aldosterone, and MRAs even lead to overexpression of aldosterone. Additionally, some studies demonstrate that the current clinical practice of using MR antagonists for primary hyperaldosteronism fail to abrogate the excess risk for cardiometabolic outcomes (primary outcome) as well as death, atrial fibrillation, and diabetes (secondary outcomes) compared with similar patients with essential hypertension and, therefore, a more aggressive and multi-faceted approach to medical therapy may be needed.

Aldosterone synthase (AS, CYP11B2) inhibitors (ASI) attenuate the production of aldosterone directly, predicted to have a distinct pharmacodynamics profile and have been proposed as an alternative to MRAs and RAS blockers.

Additionally, cortisol synthase (CS, CYP11B1) is an enzyme closely related to AS and responsible for generating the important glucocorticoid cortisol, required for maintaining critical metabolic and immune responses. The importance of selectivity against CS is shown by early examples of ASIs, that were only modestly selective and as such, attenuated cortisol responses when evaluated in patients. The enzymes encoded by these CYP11B1 and CYP11B2 genes share 93% amino acid sequence identity.

The project aims to discover a selective CYP11B2 inhibitors – a first-in-class drug, that doesn’t show suppression of CYP11B1 and other human CYPs, having an excellent efficacy and selectivity profile.

anti-TB drug

Worldwide, TB is one of the top 10 causes of death and the leading cause from a single infectious agent (above HIV/AIDS). Millions of people continue to fall sick with TB each year. In 2017, TB caused an estimated 1.3 million deaths (range, 1.2–1.4 million)2 among HIV-negative people and there were an additional 300 000 deaths from TB (range, 266 000–335 000) among HIV-positive people. Globally, the best estimate is that 10.0 million people (range, 9.0–11.1 million) developed TB disease in 2017: 5.8 million men, 3.2 million women and 1.0 million children.

Mycobacteria tuberculosis can develop resistance to the antimicrobial drugs used to cure the disease. Multidrug-resistant TB (MDR-TB) is TB that does not respond to at least isoniazid and rifampicin, the 2 most powerful anti-TB drugs. In 2016, an estimated 490 000 people worldwide developed MDR-TB, and an additional 110 000 people with rifampicin-resistant TB were also newly eligible for MDR-TB treatment. The countries with the largest numbers of MDR/RR-TB cases (47% of the global total) were China, India and the Russian Federation. It is estimated that about 6.2% of these cases were XDR-TB. Moreover, strains resistant to all existed drugs (TDR-TB) have been reported in recent years.

In some countries, it is becoming increasingly difficult to treat MDR-TB. Treatment options are limited and expensive, recommended medicines are not always available, and patients experience many adverse effects from the drugs. In some cases even more severe drug-resistant TB may develop. Extensively drug-resistant TB, XDR-TB, is a form of multidrug-resistant TB with additional resistance to more anti-TB drugs that therefore responds to even fewer available medicines. It has been reported in 117 countries worldwide. [1]

The complexity of mycobacterial infection determines the complications in antimycobacterial drug development. Current options require drug combination and treatment protocols of long duration. It is almost impossible to eliminate all TB cells from human organism with any available drug. Besides standard challenges in drug development related to PK and metabolism profile anti-TB drugs should overcome several additional barriers. M. tuberculosis has a formidable barrier for anti-TB drug in its lipid-rich cell wall. Although they are Gram-positive organisms, the mycobacterial cell wall resembles the outer membrane of Gram-negative bacteria, since it is composed of an asymmetric bilayer containing distinctive mycolic acids, as well as a range of other lipids, glycolipids, lipoglycans, and proteins. During human disease, bacteria are found both inside macrophages and extracellularly in granulomas (which can be hypoxic and/or acidic) or in cavities. A poor understanding of the physicochemical properties required for effective antimycobacterial drug penetration through all human and TB organism’s barriers further complicates drug delivery and stability options through the development.

This explains a high demand of pharmaceutical market in appearance of novel anti TB agents directed to new pathogen targets and able to significantly improve current treatment protocols.

Discovery and validation of new molecular targets is extremely important for the development of innovative anti-TB agents. Mycobacterium tuberculosis (MT) genome revealed unexpectedly large number of cytochromes P450 (CYP) – 20 isoforms that are highly conserved among pathogenic mycobacteria and some of them have been associated with virulence. Blocking MT CYPs activity is a potential pharmacological therapy of TB [2].

During the project we evaluate the possibility to target CYPs of MT. We analyzed CYPs genes of drug-resistant and drug-sensitive strains MT strains from the Tuberculosis Portals program (TBPP) database [3] and revealed the absence of nonsense or frameshift mutations in most enzymes. Moreover, for some CYP proteins, a high degree of correlation between amino-acid substitutions and the development of resistance to certain type of antibiotics was observed. Next, we purified and assessed the drugability of selected CYPs. We showed for the first time that novel drug SQ109 (Phase II clinical trials) can be metabolized by MT CYP suggesting that this isoform could represent drug-metabolizing analogous of human CYPs. On the other hand, we revealed that MT CYPs could be involved in modulation of oxysterol and vitamin D synthesis [4] that might be another adaptation mechanism of mycobacteria to escape human immune system.

Inspired by accumulated scientific data MT-Medicals LLC develops first-in-class anti-tuberculosis drug that targets certain CYPs of mycobacteria. The project is currently at hit-to-lead optimization stage.

Advancing MT CYP targets for the development of selective inhibitors has the potential to produce new drugs with novel mechanisms of action and benefit TB patients worldwide.

References:

1. Global TB report 2018. WHO.

2. Potential drug targets in the Mycobacterium tuberculosis cytochrome P450 system. Ortiz de Montellano PR. J Inorg Biochem. 2018; 180:235-245.

3.  The TB Portals: an Open-Access, Web-Based Platform for Global Drug-Resistant-Tuberculosis Data Sharing and Analysis. Rosenthal A et al. J Clin Microbiol. 2017; 55(11):3267-3282.

4. Identification of Mycobacterium tuberculosis enzyme involved in vitamin D and 7-dehydrocholesterol metabolism. Gilep AA. et al. J Steroid Biochem Mol Biol. 2017;169:202-209.

pipeline potential

We are contantly improving our technological platrofm CRYSTA in order to maintain a future potential by aiming a several perspective indications:

  • antrogen-dependent pathologies
  • fungal infection 
  • chronic kidney disease
  • anti-inflammatory
  • anti-thrombotic
  • Alzheimer's disease