The chemical sciences, and chemical biology in particular, have great potential for translational applications as much of the research examines topics within a biological context. The Rullo Lab is an amazing example of this, as they are situated at the interface of medicine and chemical biology, focusing on translational research between the two.Â
The lab is led by assistant professor Anthony Rullo, who started his academic journey here at McMaster and has come full circle now operating his own lab at the university. Anthony specialized in biochemistry during his undergraduate degree at McMaster, and went on to do his master’s studies in the Monteiro lab at the University of Guelph, and rounded off his graduate studies under Dr Mark Nitz at the University of Toronto. Dr Rullo completed his postdoctoral fellowship at Yale University in Connecticut and is now appointed as an assistant professor in the Department of Chemistry and Chemical Biology as well in the Department of Medicine. Â
Getting back to the lab itself, the bulk of their work revolves around developing both covalent and multivalent proximity inducing strategies, which are techniques that allow ligands to bind to non-traditional substrates. In addition to this, many of their studies also aim to look at biomolecule labeling chemistry, physical organic chemistry, and carbohydrate chemistry.Â
Looking at their proximity inducing strategies, let’s take a look at one of their breakthrough studies released in the past few years, where they demonstrate the functionality of a newly developed covalent proximity-induction strategy using bifunctional peptides. To begin understanding this, we need to first recognize that a proximity-induction strategy is one that brings ligands, such as antibodies, to substrate sites, such as tumours, in a fashion that does not occur innately, using the support of an additional peptide. Because this is not an endogenous process, it requires external support, and this is where the proximity-induction strategy comes into play. Ultimately, it allows two things to be brought together that normally do not interact, and this is an important area of study when the outcome of the two things being brought together is largely positive, such as being able to hone in on a previously untargetable tumour.
With the significance understood, let’s look at how they made it happen. The support peptide they used to bring together the ligand and substrate is a bifunctional one, which was created by converting a specific glycoprotein peptide into a shorter peptide with a newly attached electrophilic covlent handle and a tumour-binding site (Figure 1). They now had a molecule with the potential to bind both antibodies at the electrophilic site, and tumours via the tumour targeting moiety, and so the last step was to determine the antitumour efficacy of their bifunctional peptide.
Figure 1: The creation of the bifucntional peptide starts with taking an exerpt of a glycoprotein peptide, followed by several modifcations to the peptide in order to optimize for its purpose.
The results showed that the electrophilic region of the bifunctional peptide was able to both selectively and irreversibly target their desired antibodies, and the reaction rate could be tuned as needed by modifying the electrophilic region. Additionally, the peptide was able to successfully bind to tumour binding sites, meaning that they were able to successfully bring antibodies within proximity of tumours, which allows for binding that was not previously possible. This resulted in successful immunotherapeutic capacity that was characterized by enhanced anti-tumour efficacy when contrasted with similar peptides without electrophilic recruiting regions.
Evidently, the Rullo lab created a immunotherapeutic bifunctional peptide that successfully encapsulated their proximity-induction strategy. This therapy has great potential as it allows the immune system to harness antibodies for purposes previously unused, and they believe that it will have future utility with anti-viral antibodies in synthetic tumour immunotherapy. The Rullo lab is constantly investigating interesting things, so click on this link to read some of their latest publications: https://www.rullolab.com/publications
The finding of this work has been published in ACS Chemical Biology: McCann, H. M.; Lake, B. P. M.; Hoffman, K. S.; Davola, M. E; Mossman, K. L.; Rullo, A. F. Covalent Immune Proximity-Induction Strategy Using SuFEx-Engineered Bifunctional Viral Peptides. ACS Chem. Biol. 2022, 17 (5), 1269-1281. https://doi.org/10.1021/acschembio.2c00233