Research Projects
Research in Boudreault’s laboratory is focused on medicinal chemistry, specifically at the interface between chemistry, pharmacology, biochemistry, and molecular modeling. With strong expertise in organic chemistry, small molecules, natural product derivatives, peptides and peptidomimetic synthesis, and molecular modeling are used as a tool to address and understand problems of significance in bioorganic and medicinal chemistry. A particular emphasis is placed on the design, synthesis and biological characterization of new molecular entities, their interactions with receptors and other cellular biochemical systems, as well as the optimization of their pharmacodynamic and pharmacokinetic properties.
A collaborative approach is privileged to select potential therapeutic targets to be studied in relation to the development of small molecule enzymatic modulators, the modulation of protein-protein and protein-biomolecule interactions, the modulation of GPCRs, TTSPs, the design, the study, and the use of mono- and bi-cyclic molecular systems allowing the optimization of the structure-activity relationship and their pharmacokinetic properties, the development of peptidomimetic molecules and the development of antibodies and bioconjugates.
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Exploration of GPCRs chemical space
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G protein-coupled receptors (GPCRs) constitute the largest family of membrane receptors and the target of about 40% of drugs. In this family, our research work focuses on the design of ligands capable to bias peptidergic receptors signaling such as APJ (apelin hormone target), NTS1/NTS2 (neurotensin hormone target) and AT1 (angiotensin II type 1) receptors. Biased signaling is a relatively new concept, which aims to favor specific signaling pathways. Conceptually, this would allow to bias signaling pathways toward the desired effects at the expense of signaling pathways leading to adverse effects by modulating ligand structure. With the help of molecular modeling, our objective is also to better understand the structure-activity relationship between the ligand and the receptor in order to optimize the pharmacological properties of the molecules towards potential therapeutic candidates.
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Macrocycles
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Macrocycles are a unique chemical class which combine the ability to display distant pharmacophores while keeping a semi-rigid structure. Therefore, they have the potential to combine the benefits of large molecules in terms of structural information content and the benefits of small molecules in term of PK-ADME. Several projects involving macrocycles are ongoing, with the goal to inhibit protein-protein interactions, improve intestinal absorption and modulate GPCRs signalisation.
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Novel molecular transporters for cell penetration
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We develop new molecular transporters capable to help impermeable molecules cross cell membranes. In the long term, we target the development of vectors capable to discriminate different cellular types for targeted drug delivery.
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Inhibitors of type 2 transmembrane serine proteases (TTSPs)
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In this class of protein, we focus on matriptase, matriptase 2 and TMPRSS2, TMPRSS13. We have designed a new class of peptidomimetic inhibitors that display efficacy to inhibit the replication of the H1N1. We also identify and characterize a small-molecule compound, as the most potent inhibitor of TMPRSS2 reported to date, inhibiting SARS-CoV-2 infection in human lung cells. This compound acted as a broad-spectrum coronavirus inhibitor of two SARS-CoV-2 VOCs, B.1.1.7 and B.1.351.
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Emerging class of antibiotics
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Riboswitches are secondary RNA structures that controle a specific genetic operon. Inhibiton of certain riboswitches is emerging as a promising target against multiresistant pathogens such as methycillin resistant Staphylococcus aureus (MRSA) or Clostridium difficile. Our group also is interested in teixobactin. Discovered in 2015, teixobactin is a macrocyclic depsipeptide that possesses antibacterial activity in Gram positive bacteria, including the most resistant. There is no strain of bacteria that developped a known resistance to this antibiotic so far. A Trojan horse-like strategy would likely allow teixobactin to have activity against Gram-negative bacteria.
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