Engineering a Coiled-Coil Protein for DARPin Presentation as a Potent SARS-CoV‑2 Therapeutic

TL;DR

Researchers designed a new protein therapy that can quickly adapt to SARS-CoV-2 variants and showed it works well in mice.

Contribution

A modular fusion protein platform combining DARPins and a coiled coil for adaptable and effective antiviral therapeutics.

Findings

HEX-DARPins neutralized multiple SARS-CoV-2 variants effectively in pseudovirus tests.

Albumin binding improved HEX-DARPin delivery to the lungs and prolonged serum concentration in mice.

The platform is adaptable for future viral threats and offers advantages over monoclonal antibodies.

Abstract

The COVID-19 pandemic has 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 as neutralization
therapies is challenging, given their size, production complexity,
and cost. Here, 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 (CC-HEX).
The fusion proteins are modular, suitable to rapidly adapt to new
variants or pathogens, and enable the incorporation of both viral
and serum albumin-binding functions. We demonstrated potent neutralization
by HEX-DARPins against multiple variants of the SARS-CoV-2 pseudovirus.
Albumin binding prolonged serum concentration and improved delivery
to the lungs in mice. This work establishes HEX-DARPin fusion proteins
as potential therapeutics for the treatment of COVID-19 and as a platform
for the development of drugs against future viral pathogens.

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