De novo design of cytokines, antikines, and novokines

Cytokines are key signaling molecules critical for multiple aspects of health and disease. This motivated the development of modulators of cytokine signaling as part of the course of treatment for several types of malignancies. Developing protein-based modulators of these pathways has nevertheless been restricted to classical approaches such as recombinant cytokines (i.e. agonists) and monoclonal antibodies (i.e. antagonists). Our work deploys cutting-edge de novo protein design techniques to create and develop novel proteins with superior pharmaceutical properties compared to existing classes. These designed mini-proteins can bind cytokine receptors to either activate or inhibit their native signaling. Moreover, we could create single-domain proteins that encode two distinct receptor binding sites (novokines). These novokines can bind and dimerise non-native combinations of cytokine receptors, and depending on the context, can play novel pharmacological roles. Taking the granulocyte-colony stimulating factor receptor (G-CSFR) as an example, we will discuss our ongoing work that could achieve potent activators, inhibitors, and novel modulators.

Publication History

Article published online:
17 May 2022