# The computationally designed TRI2-2 miniprotein inhibitor protects against multiple SARS-CoV-2 Omicron variants

## TL;DR

A computationally designed miniprotein called TRI2-2 can protect against multiple SARS-CoV-2 Omicron variants in mice.

## Contribution

TRI2-2 is a novel, computationally designed miniprotein that shows broad neutralizing activity against emerging SARS-CoV-2 variants.

## Key findings

- TRI2-2 protects mice against BQ.1.1, XBB.1.5, and BA.2.86 SARS-CoV-2 variants when administered intranasally.
- TRI2-2 is resistant to viral escape by most variants and can be delivered directly to the upper airways.

## Abstract

The continued evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has compromised neutralizing antibody responses elicited by prior infection or vaccination and abolished the utility of most monoclonal antibody therapeutics. We previously described a computationally-designed, homotrimeric miniprotein inhibitor, designated TRI2-2, that protects mice against pre-Omicron SARS-CoV-2 variants. Here, we show that TRI2-2 exhibits broadly neutralizing activity of SARS-CoV-2 variants and protects mice against BQ.1.1, XBB.1.5 and BA.2.86 challenge when administered intranasally post-exposure. The resistance of TRI2-2 to viral escape by most variants and the ability to deliver it directly to the upper airways highlight the potential of the multivalent miniprotein inhibitor as an alternative therapeutic modality.

Computationally designed TRI2-2 miniprotein inhibitor broadly neutralizes multiple SARS-CoV-2 Omicron variants and confers post-exposure protection in mice against BQ.1.1, XBB.1.5, and BA.2.86 challenge when administered intranasally.