Catalysis deactivated angiotensin-converting enzyme 2 (ACE2) variants and their uses

Inventors

Liu, Shengjiang

Assignees

Avirmax Inc

Abstract

Angiotensin-converting enzyme 2 (ACE2) has been confirmed as a specific receptor for several β group coronaviruses include severe respiratory syndrome (SARS) coronavirus (SARS-CoV-1) and recently the causative agent for the World pandemic CoVID-19, SARS-CoV-2, and low pathogenic coronavirus of HCoV-NL63, a member in α-coronavirus group. Viral spike protein (S) of viral envelope is confirmed to bind to ACE2 as viral receptor to start a virus replication cycle. The present invention provides ACE2 and its mutants or variants, the viral or non-viral vectors thereof. Methods of treatment of viral infection of a human subject by using such mutants or variants are also provided.

Core Innovation

The disclosed subject matter provides ACE2 variants that lose catalytic activity while retaining or enhancing binding to coronavirus spike (S1) proteins. The variants include mutations that alter the metal-ion binding motif (HEXXH…E) and related catalytic residues, including H374, E375, H378, E402, R273, H345, P346, H505, and H515, and the resulting ACE2 extracellular domain is described as catalytically deactivated and referred to as ACE2-vECD.

The ACE2 variants and polypeptides are configured to maintain spike binding through changes focused on zinc-motif and associated catalytic residues, while preserving the ability to bind coronavirus spike proteins. The document describes ACE2 extracellular domain (ACE2-ECD) and ACE2-vECD as Fc fusions, including ACE2-ECD-Fc and ACE2-vECD-Fc, using human IgG Fc, and reports binding/affinity measurements for interactions with SARS-CoV-2 and MERS-CoV-1.

The document further provides nucleic acids encoding the ACE2 constructs and expression systems that support therapeutic and preventive use. It describes isolated polynucleotides and vectors for delivery, including viral vectors and non-viral vectors, and states therapeutic concepts including urgent treatment and vaccine concepts enabled by long-acting in vivo expression, with targets explicitly stated as SARS-CoV-1, SARS-CoV-2, MERS-CoV-1, and HCoV-NL63.

Claims Coverage

The independent claim coverage centers on an isolated polynucleotide defined by specified sequence identifiers. The claim set also extends to vectors incorporating that polynucleotide, with refinement to viral vectors, adeno-associated virus nucleotide sequence, and optional additional carrier components.

Claim coverage is centered on an isolated polynucleotide defined by specific SEQ ID NOs, and extends to vectors incorporating that polynucleotide, particularly viral vectors with an adeno-associated virus nucleotide sequence and optional additional carrier components.

Stated Advantages

Documented Applications