Maurice Michel

Maurice Michel

Assistant Professor
Visiting address: SciLifeLab Tomtebodavägen 23a, 17165 Solna
Postal address: K7 Onkologi-Patologi, K7 Övriga Onkologi övriga forskare Michel, 171 77 Stockholm
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Research

  • Although widely used in industry, organocatalysis has classically been limited to ex vivo application. In addition, the small molecule activation of enzymes has so far been exerted by allosteric control. A union of the two concepts has classically been considered unattractive, as partaking in the reaction would require binding to the enzymatic active site. This in turn would render the molecule an inhibitor as desired high compound concentration for high reaction turnover would compete with the originally intended substrate. However, this interpretation ignores enzymes with complex biochemistry, where substrate hydrolysis is achieved by consecutive steps of replacement and cleavage. Here, the inhibition or enhancement of single steps is conceivable with more complex mode of action. Recently, we reported that small molecules can act as organocatalysts for the DNA repair enzyme 8-oxoguanine DNA glycosylase 1 (OGG1). The underlying principle allows for a full control of enzymatic function with potential for alleviating oxidative stress to the genome or as a new strategy in cancer therapy
  • please visit the document section for more details.
    To built on this discovery, we focus on three pilars, leveraging our expertise in medicinal and computational chemistry, biochemistry and biophysics and collaborate where needed. Read more about our research below:
    *1. Development of OGG1 activators:*
    In June 2022, we were first to report cellularly active organocatalysts [1] - OGG1 activators assist the enzyme in reaction turnover and diversification of substrate and product scope. Based on some of the findings, we continue to drive synthetic chemistry with help of X-Ray co-crystal structures and computational chemistry. Our goals within this context, are the exact control of product scope [2], the tuning of a defined pH range of OGG1 biochemical reactions and the selective targeting of cellular organelles. With this achieved for lead molecules, we collaborate with disease experts to reach proof of principle in disease models driven by OGG1 biology or oxidative stress to the genome in general. We also aim to understand the activation of elimination mechanisms in DNA repair by exploiting chemical principles, such as leaving group activation, proton abstraction and aldehyde tuning. Here, we are making great strides in reducing the necessary molecularity, dramatically increasing enzyme turnover.
    *2. Broadening of the technology base of enzyme activation*
    Although OGG1 is no significant AP-lyase in cells, DNA glycosylases with pronounced β- or β, δ-AP lyase activity exist in humans and other species. Understanding how these activities are controlled on a molecular level, allows us to alter enzyme function at will and thus generate new DNA repair pathways for the treatment of disease. We perform computational calculations to elucidate chemical and biochemical reaction mechanisms, generate amino acid mutants, develop organocatalysts and engineer proteins through amino acid selective modifications and bioorthogonal chemistry. The ultimate goal: enabling an array of enzymes to cleave non-natural substrates through previously unreported reaction pathways. To achieve this, we leverage our expertise in bio-macromolecules, enzymes and organocatalysis. The implications of this research reach also beyond medicine and thus we also collaborate with industry partners to impact biocatalysis.
    *3. The DNA glycosylase platform within EUbOPEN*
    Eleven human DNA glycosylases exist and most of them are considered understudied. Within the EUbOPEN [3] consortium, we assemble all of them physically, develop in vitro and cellular assays for selectivity/activity readout and target engagement. In collaboration with partners at the Structural Genomics Consortium [4] and Stockholm University [5] we assemble crystal structures, antibodies and other reagents and enable investigation of the entire protein family. We donate this setup to the scientific community through protocols within EUbOPEN [6] and Target2035 [7]. Ultimately, we thrive to combine our work on small molecule activators with these novel targets and enable the studying of DNA repair biology.
    *Michelaneous*
    We are deeply committed to mentoring, coaching, teaching and supporting the next generation of students. For example, our strategic exchange program with the Universities of St. Andrews [8] and Edinburgh [9] has led to fruitful collaborations and a uniquely educated generation [10] of undergraduate students – their success is our legacy. Reach out, if you want to work with us and shape the future in protein regulation. #MentorFirst [11]
    Our work is highly collaborative on many levels and we are happy to be working with a number of skilled scientists from different institutions and sectors:
    Crystallography – Stenmark [12], Stockholm University
  • MM/QM – Himo [13], Stockholm University
  • Protein production/antibodies – Structural Genomics Consortium [14], CMM, Sweden
  • Autophagy – Stolz [15], Frankfurt
  • Post-Translational Modifications – Knapp [16], Frankfurt
  • Drug Delivery – Windbergs [17], Frankfurt
  • CAR-T cells – Mougiakakos [18], Magdeburg/Erlangen
  • NASH – Lauschke [19], Karolinska
  • Liver fibrosis – Xia [20], Renji
  • Premature aging – Eriksson [21], Karolinska
  • Chemical Biology Consortium Sweden [22] - Project Support
  • Drug Discovery and Development Platform [23] – Project Support
  • Industrial Bio-Catalysis – RISE Södertälje [24]
  • Industrial Bio-Catalysis - SINTEF Trondheim [25]

    [1]https://www.science.org/doi/10.1126/science.abf8980
    [2]https://onlinelibrary.wiley.com/doi/full/10.1002/ctm2.1035
    [3]https://www.eubopen.org/
    [4]https://www.thesgc.org/scientists/groups/karolinska
    [5]https://www.su.se/english/profiles/stenm-1.182287?open-collapse-boxes=research-publications, research-projects, body-research
    [6]https://www.eubopen.org/protocols-reagents
    [7]https://www.target2035.net/
    [8]https://news.st-andrews.ac.uk/archive/chemistry-students-discovery-could-help-treat-alzheimers/
    [9]https://www.chem.ed.ac.uk/news-events/news/recent-graduate-published-science
    [10]https://www.st-andrews.ac.uk/chemistry/news/title-173949-en.php
    [11]https://mentorfirst.org/
    [12]https://www.su.se/english/profiles/stenm-1.182287?open-collapse-boxes=research-publications, research-projects, body-research
    [13]https://www.organ.su.se/himo/
    [14]https://www.thesgc.org/scientists/groups/karolinska
    [15]https://biochem2.com/research-group/er-quality-control#nav-about
    [16]https://www.uni-frankfurt.de/53483664/Knapp
    [17]https://www.bmls.de/Drug_Delivery_and_3R-Models/aboutus.html
    [18]https://www.medizin5.uk-erlangen.de/en/research/research/rg-mougiakakos/
    [19]https://ki.se/en/fyfa/personalized-medicine-and-drug-development
    [20]https://www.shsmu.edu.cn/english/info/1354/4092.htm
    [21]https://ki.se/en/bionut/genetic-mechanisms-of-ageing-maria-eriksson
    [22]http://www.cbcs.se/
    [23]https://www.scilifelab.se/units/ddd-platform/
    [24]https://www.ri.se/en/about-rise/about-rise
    [25]https://www.sintef.no/en/

Teaching

  • A new compound class that partakes in enzymatic reactions
    Commonly, enzymes have an active site which was designed during evolution to bind substrates with high specificity. Very robust chemical transformations dominate the identity of the generated product. Chemists can generate a “negative” imprint of the active site in form of small molecules. These bind the enzyme with higher affinity and block the chemical transformation. This process encumbers the inhibition paradigm which has been very successful in medicine. Comparably high concentrations are required to block all circulating copies of an enzyme, often leading to off-target effects.
    Chemists have also generated small molecule activators of enzymes. These are optimized for a site that is not the one performing the chemical transformation. Rather, they are placed in a position that does not obviously interfere with substrate binding. Enzymes, like all proteins, are a three-dimensional network of amino acids. These networks are responsive to binders no matter where on their surface this binding occurs. Small molecule activators induce a stabilization in the network of amino acids that stretches to the active site. Here, substrate binding, a short-lived intermediate or product release can be favored. Small molecule activators may not change any of the identities of reactants or products but merely increase their conversion or generation. Per definition small molecule activators cannot bind the active sites, since this would render them an inhibitor. Comparably high concentrations are necessary to bind, but not required to see an effect. Activation may suffice at a level as low as 10-20%.
    We were first to use small molecules that enhance enzyme functions from within the active site. They exert their effect by rewriting the chemical transformation base of the enzyme. Part of the organocatalytic switches convey affinity to the enzyme and another part partakes in a chemical transformation. The molecule leaves the reaction unchanged and subsequently may move on to further copies of the enzyme. This is what a catalysts does.
    This concept may or not be beneficial for the purpose of increasing the enzyme function. If it is, the functional enhancement is beyond what is commonly observed, since the compound can do the reaction over and over again.
    For the case of our enzyme, the rewriting of chemical transformation is so dominant, that is also changes which substrates are accepted. This shifts the enzyme function from removing damaged guanines to removing nucleobase gaps in DNA. The latter is more abundant in cells that are under stress and is also generated by diverse processes. The enzyme is therefore rewritten to a cellular cleaner of a major insult to our genome.
    Depending on which small molecule we use, we may also decide which product is generated during the chemical transformation. This can either enhance repair of damage to the genome in a beneficial sense or overload pathways which have not evolved to maintain this kind of lesion load. In the former, we can use the compounds to increase the bodies repair function in age-related diseases or inflammation. In the latter, we artificially shape new dependencies which can be exploited in cancer therapy. Expanding the concept to proteins that generate confusing new products will be key for the exploitation in precision medicine.

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