Natural product-inspired small molecule for the therapy of cognitive impairment associated with depressive disorder and other CNS diseases

Cognitive impairments, often seen in conditions like major depressive disorder, Alzheimer’s disease, Parkinson's disease, and other CNS disorders, involve disruptions in normal thinking, learning, and memory. While there is no cure, certain drug classes, such as antidepressants, may help slow memory loss progression.
Our research project focuses on the discovery and development of a small-molecule drug candidate to treat or at least alleviate cognitive deficits. The central chemical core is vindeburnol, a synthetic derivative inspired by the structure of the eburnamine-vincamine alkaloids, known for its fascinating pharmacological effects. Our rigorous behavioral-driven medicinal chemistry aims to fine-tune this core and identify a molecule that improves memory and diminishes depression-like behavior in rodents. We’ll conduct in vitro ADME-T studies, including blood-brain barrier permeability, as well as some biochemical measurements, such as assessment of monoamine content in distinct regions of the brain, to reveal optimized leads. To shed some light on the mechanism of action, we’ll carry out receptor binding and functional assays.
This research project is being conducted with V. Serbsky National Medical Research Center for Psychiatry and Narcology and with a grant from R-Pharm.

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Non-nucleoside reverse transcriptase HIV-1 inhibitors

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are a critical component of antiretroviral therapy (ART), essential for effectively managing HIV infection. These small molecules bind to and block reverse transcriptase, a key enzyme in the virus's replication machinery, thereby preventing viral replication.
Our research project focuses on the discovery of novel NNRTIs with enhanced potency and reduced CNS toxicity. Through rigorous screening, we have tested over 100 derivatives to identify crucial structural features. As a result, the small molecule 12126065 was demonstrated robust in vitro activity against wild-type strain and clinical mutants of HIV. This compound shows favourable in vivo toxicity and pharmacokinetic profiles. Notably, it lacks the neuronal toxicity associated with the standard efavirenz. Efficacy studies are currently in progress.
This research project is being carried out in partnership with Collaboration Pharmaceuticals, the University of North Carolina, and the University of Cagliari.

Small-molecule protein kinase inhibitors

Cancer is a leading cause of death worldwide. Over time, cancer cells become resistant to available drugs. Addressing this challenge calls for the discovery of next-gen inhibitors and improved combination therapy.
This project aims to discover and develop a safe and effective drug candidate based on the thiophene scaffold to treat a specific type of cancer by targeting protein kinases. Our lab utilizes the NCI60 screening to conduct early-stage structure-activity relationship studies of this chemical class.
Certain molecules from our lab library exhibit remarkable efficacy, demonstrating up to 85% growth inhibition against melanoma and central nervous system cancer cells in vitro.
We are actively pursuing precise protein kinase and in vitro ADME-T profiling to select candidates for in vivo toxicity and efficacy studies.
This research project is being carried out in partnership with Collaboration Pharmaceuticals.
Key publications:
  1. Multiple approaches to repurposing drugs for neuroblastoma. Bioorganic and Medicinal Chemistry, 2022

Search for M. tuberculosis resuscitation promoting factor inhibitors

Dormant state is one of the main features of Mycobacterium tuberculosis to avoid elimination from the human body. In this state, the so-called Mtb persistes have reduced sensitivity to first- and second-line TB drugs and are able to switch to the active state, provoking TB relapse. Mycobacterial resuscitation-promoting factors (Rpfs) are known to be involved in this reactivation process.
Our research aims to discover small-molecule chemical probes that selectively target this enzyme in order to find more potent compounds capable of inhibiting Rpf-mediated reactivation process.
This research is being carried out in partnership with the University of Leicester.

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Dispirotripiperazine as an unusual scaffold for new antivirals

Dispirotripiperazines are tricyclic molecules with two shared atoms, or “spiro atoms”. A unique feature of these compounds is the presence of two quaternary positively charged nitrogen atoms in their structure, the meaning of which is not fully understood and is the subject of study. It is assumed that these atoms may be responsible for electrostatic interactions with the negatively charged host cell-surface heparan sulfate residues, involving in host-pathogen interactions.

PDSTP, the most important member of this chemical class to date, inhibits in vitro a panel of viruses known to use heparan sulfate for early interaction with host cells. The molecule recently demonstrated fascinating efficacy in a rabbit model of herpes simplex epithelial keratitis.

This research is being carried out in partnership with the Charité – Berlin University of Medicine and the University of Cagliari.

Efficacy of PDSTP in a rabbit model of eye keratitis

Chemical probe C109 blocking the bacterial protein FtsZ

Filamenting temperature-sensitive mutant Z (FtsZ) is a key cell-division protein in a range of bacteria, such as Acinetobacter baumannii, Pseudomonas aeruginosa, Staphylococcus aureus (these bacteria are included in the WHO priority pathogens list), and Burkholderia cenocepacia.
An in-house library screening revealed that the benzothiadiazole compound C109 could inhibit the growth of Burkholderia cenocepacia, Pseudomonas aeruginosa, Staphylococcus aureus, and Acinetobacter baumannii. In addition, the compound could specifically block the GTPase activity of the FtsZ protein, making it a good starting point for antibacterial drug discovery campaigns.
This research is being carried out in partnership with the University of Pavia.
Influence of molecule C109 on the Staphylococcus aureus biofilm formation

Chemical probe TP053 active against replicating and non-replicating M. tuberculosis

Inspired by the interesting pharmacological properties of the thieno[2,3-d]pyrimidine scaffold, we decided to explore this core against Mycobacterium tuberculosis. Structure-activity relationship studies led to the selection of the compound TP053, which exhibits low minimal inhibitory concentration values against replicating (H37Rv) and non-replicating (ss18b) Mtb.
TP053 acts as a prodrug against Mtb H37Rv through its activation by mycothiol-dependent nitroreductase Mrx2. Transformation of TP053 involves cleavage of the fused thiophene ring and nitric oxide (I) release, which contributes to activity against non-replicating Mtb. The resulting highly reactive metabolite also promotes activity against replicating bacteria. Further studies are ongoing.
This research is being carried out in partnership with the University of Pavia.

Small-molecule inhibitors of Picornaviridae entry

The common cold is predominantly caused by entero- or rhinoviruses. These viruses belonging to the Picornaviridae family have a so-called "pocket" on the viral capsid surface responsible for attachment to the host cell and subsequent infection. Being an attractive target, this pocket can be bonded by small molecules called "capsid binders".

Our medicinal chemistry efforts are focused on a comprehensive structure-activity investigation of two distinct small-molecule scaffolds. The pyrazolo[3,4-d]pyrimidine-based OBR-5-340 and the pleconaril-core cmpd 10g (see ref #4), selected as lead molecules, are being studied in-depth.
It was unexpectedly found that OBR-5-340 (named SCO-201) could act as an ATP-binding cassette transporter modulator to reverse cancer drug resistance.
OBR-5-340 and its binding in the rhinovirus pocket

Benzothiazinones as a promising class of potent anti-TB agents

We have a long-standing interest in developing effective TB drugs. In cooperation with several European partners and with the financial support of the European Commission, we made a significant breakthrough in 2007-2008 with the discovery of the benzothiazinones, a novel chemical entity of potent anti-TB agents. These molecules served as the chemical probe that led us to identify a new Mtb target – the enzyme decaprenylphosphoryl-β-d-ribose-2'-epimerase, or DprE1, which plays a key role in the synthesis of the mycobacterial cell wall.
The compound PBTZ169 was selected from the BTZ043-to-lead optimization phase. As a result, this molecule exhibits superior in vitro activity against multidrug- and extensively drug-resistant Mtb strains and clinical isolates. Subsequently named INN macozinone, PBTZ169 showed favourable efficacy and safety profiles not only in animal models but also in clinical trials (NCT03423030, NCT03036163, NCT03776500, NCT04150224, NCT03334734).
PBTZ169 (Macozinone) and and DprE1 enzyme-PBTZ169 crystal complex
Innovation Medicine for TB | TEDxPokrovkaSt
New anti-TB molecule