L.H. Mai, J.A. Champion
Georgia Institute of Technology,
United States
Keywords: protein, valency, neutralization
Summary:
The COVID-19 pandemic demonstrated the need for rapid, flexible and readily adaptable treatment options for future pandemic preparedness. Due to the speed at which viruses like SARS-CoV-2 mutate, the customary approach of using highly specific monoclonal antibodies (mAbs) as neutralization therapies is challenging because of their size, production complexity and cost. To address this problem and improve the binding valency over antibodies, we leveraged rational protein design to create fusion proteins from small, antibody-mimetic proteins, Designed Ankyrin Repeat Proteins (DARPins) and a self-assembling hexameric coiled coil (HEX). The fusion proteins are modular, making them more suitable to be rapidly adapted to new variants or pathogens, and enabled incorporation of both viral and serum albumin binding functions. Here, we discuss fusion protein design and its effect on viral neutralization, half-life and biodistribution to establish HEX-DARPin fusion proteins as potential therapeutics for treatment of COVID-19 and as a platform for development against future viral pathogens.