Advances in developing ACE2 derivatives against SARS-CoV-2

Nasal spray of an IgM‐like ACE2 fusion protein HH‐120 accelerates SARS‐CoV‐2 clearance: A single‐center propensity score‐matched cohort study

“…have been developed 24 . The efficacy of these ACE2‐based interventions against SARS‐CoV‐2 infection is being investigated with variable outcomes 38 . HH‐120 is a multivalent recombinant IgM‐like ACE2 with exceptionally high binding avidity for the viral spike protein (>1.0 × 10 −12 M), showing about a 100‐fold higher neutralization activity than the Fc‐tagged bivalent hACE2 (ACE2‐hIgG1) and with no infection enhancement effect, which was observed in other recombinant ACE2 proteins containing most of the collectrin domain at low concentrations 26,39 .…”

“…24 The efficacy of these ACE2-based interventions against SARS-CoV-2 infection is being investigated with variable outcomes. 38 HH-120 is a multivalent recombinant IgM-like ACE2 with ), showing about a 100-fold higher neutralization activity than the Fc-tagged bivalent hACE2 (ACE2-hIgG1) and with no infection enhancement effect, which was observed in other recombinant ACE2 proteins containing most of the collectrin domain at low concentrations. 26,39 Furthermore, unlike other ACE2 derivatives that have limited local bioavailability when administered through infusion, delivering HH-120 directly to the upper respiratory tract has shown sufficient drug exposure to effectively contain the virus while also offering expected dose-sparing benefits.…”

A Piecewise Design Approach to Engineering a Miniature ACE2 Mimic to Bind SARS-CoV-2

“…Human recombinant soluble ACE2 (hrsACE2) has emerged as a promising candidate, demonstrating notable success in clinical trials by effectively reducing viral load . A strategic consideration in the development of soluble ACE2 involves the introduction of escape mutations, aiming to foster forms of the spike protein that diminish infectivity, thereby slowing the mutation of increasingly infectious SARS-CoV-2 variants . However, the practical implementation of soluble ACE2 as a therapeutic hinges on the ability to purify substantial quantities of the protein.…”

“…42 A strategic consideration in the development of soluble ACE2 involves the introduction of escape mutations, aiming to foster forms of the spike protein that diminish infectivity, thereby slowing the mutation of increasingly infectious SARS-CoV-2 variants. 13 However, the practical implementation of soluble ACE2 as a therapeutic hinges on the ability to purify substantial quantities of the protein. Addressing this challenge, utilizing solubility-increasing mutations becomes crucial, significantly aiding the production yield.…”

“…In the realm of scientific advancements, the reduction in the size of ACE2, enhancement of binding affinity to spike RBD, and increased solubility have emerged as key factors for improving cellular transmissibility and tissue penetration. Since the onset of the COVID-19 pandemic, numerous studies have delved into the optimization of ACE2 size, comparing the spike RBD binding capabilities of small synthesized peptides derived from truncated ACE2. − Simultaneously, other research groups concentrated on elevating the affinity between ACE2 and spike through computational methods or directed evolution mutagenesis, pinpointing ACE2 point mutations for heightened binding affinity. − We have integrated these approaches enabling the engineering of a soluble ACE2 variant that amalgamates the advantages of reduced size and enhanced spike affinity. Most previous studies also utilized chemically synthesized peptides, and while chemical synthesis allows for the generation of high-purity peptides, its cost-prohibitive nature becomes apparent when large quantities are required. , In a bid to streamline production efficiency and economize time, we further fine-tuned the solubility of our recombinantly produced ACE2.…”