RESEARCH / Molecular therapeutics
Prior to moving to Heidelberg, the Joazeiro Laboratory was at the Genomics Institute of Novartis (GNF) and then at Scripps Research, both in San Diego, California. At GNF, we worked on the identification and validation of drug targets in the ubiquitin system and carried out drug discovery activities related to those targets. We now leverage this Industry experience and our knowledge on RQC and unique model systems to discover small molecules that can either be used as research tools or be developed as pharmaceutical drug candidates.
Coopting new E3 ubiquitin ligases to develop protein degraders (PROTACS) for therapeutic applications
Protein degraders (PROTACS and Molecular Glues) are small molecules that act by bringing together an E3 ligase with a protein of interest (‘neo-substrate’), thereby promoting ubiquitination and degradation of the latter. Degraders engineered for therapeutic applications are already advancing through clinical trials with promising results.
We have identified and mapped over 650 E3-encoding genes in humans (Li et al. 2008; Deshaies & Joazeiro 2009). However, only a handful of those have been coopted for protein degrader development. In one line of work, we are screening for small molecules that bind to previously unexploited E3 ligases in order to develop PROTACS that may offer advantages over E3s that are currently employed.
Identifying novel molecular targets to modulate RQC
In addition to playing a role in neurodegeneration, preliminary studies associate declining RQC activity with ageing. Accordingly, we are mining for small molecule modulators of the pathway that may serve as therapeutics for neurodegeneration and other ageing-related diseases. Contact us for further details!
Addressing unmet medical needs
Despite the development of vaccines against SARS-COV-2 at unprecedented speed, COVID-19 remains an unmet medical need, as vaccines are failing to provide long term herd immunity. Clearly, therapeutics will be needed on an ongoing basis for continuing infections even after the current pandemic subsides, just as Tamiflu and Relenza are needed as continuing therapeutics for influenza, which recurs on an annual basis. To address this issue, we are developing PROTACS against essential SARS-COV-2 proteins as part of a large consortium of Industry and Academic laboratories funded by the German Federal Ministry of Education and Research (BMBF).