tetano
Editor, Senior Moderator
Antimicrob Agents Chemother
. 2026 Mar 23:e0002426.
doi: 10.1128/aac.00024-26. Online ahead of print.
Multifunctional ACE2-nanobody fusion design for pan-specific neutralization and cardiovascular protection in SARS coronavirus infection
Traian Sulea[SUP] 1 2 [/SUP], Matthew Stuible[SUP] 1 [/SUP], Maria Moreno[SUP] 3 [/SUP], Alex Pelletier[SUP] 1 [/SUP], Martin A Rossotti[SUP] 3 [/SUP], Yuneivy Cepero-Donates[SUP] 1 [/SUP], Jacqueline Slinn[SUP] 3 [/SUP], Patrick Salois[SUP] 1 [/SUP], Anh Tran[SUP] 3 4 [/SUP], Melissa Hewitt[SUP] 3 [/SUP], Alvaro Yogi[SUP] 3 [/SUP], Nazanin Rohani[SUP] 1 [/SUP], Brian Cass[SUP] 1 [/SUP], Anne E G Lenferink[SUP] 1 [/SUP], Jamshid Tanha[SUP] 3 4 5 [/SUP], Binbing Ling[SUP] 3 [/SUP], Etienne Lessard[SUP] 1 [/SUP], Laurence Delafosse[SUP] 1 [/SUP], Jagdeep K Sandhu[SUP] 3 [/SUP], Danica Stanimirovic[SUP] 3 [/SUP]
Affiliations
Severe acute respiratory syndrome coronaviruses use the ACE2 receptor for viral entry while downregulating its activity, potentially leading to hypertension and major organ injuries. Dual-action technologies based on soluble ACE2 aimed to neutralize the virus while restoring ACE2's normal enzymatic activity. Here, we describe a novel general molecular design, VHH[SUB]Spike[/SUB]-ACE2[SUB]ECD[/SUB]-VHH[SUB]Albumin[/SUB], in the toolbox of ACE2-centric therapeutic modalities. The optimized nanobody module VHH[SUB]Spike[/SUB] afforded strong pan-specific binding against the entire sarbecoviral clade. This correlated with potent in vitro neutralization of pseudotyped virus variants of concern, with IC[SUB]50[/SUB] values in the picomolar range. Exogenous enzymatic activity was provided by the ACE2[SUB]ECD[/SUB] module, which also contributed binding avidity via intrinsic homodimerization. Persistence of enzymatic activity in circulation was increased in vivo via the nanobody module VHH[SUB]Albumin[/SUB] optimized for serum albumin binding. Single-dose therapeutic administration of lead compound 72opt-ACE2-R28 demonstrated virus neutralization in lungs of hamsters at day 5 post-infection with SARS-CoV-2. In hypertensive mice maintained under continuous injection of angiotensin II, a single dose of 72opt-ACE2-R28 normalized systolic blood pressure, maintaining a 30 mmHg reduction after 24 h. Overall, encouraging coronavirus neutralization and hypertension reduction showed magnitudes and timeframes appropriate for treatment of typical acute infections. We discuss molecular bases of interactions with coronavirus spike protein molecules and future scale-up manufacturability toward clinical development of this modular design scaffold with high potential against emerging SARS-CoV-2 variants.
Keywords: ACE2 enzyme activity; COVID-19; albumin binding; blood pressure reduction; single-domain antibody; spike protein; virus neutralization.
. 2026 Mar 23:e0002426.
doi: 10.1128/aac.00024-26. Online ahead of print.
Multifunctional ACE2-nanobody fusion design for pan-specific neutralization and cardiovascular protection in SARS coronavirus infection
Traian Sulea[SUP] 1 2 [/SUP], Matthew Stuible[SUP] 1 [/SUP], Maria Moreno[SUP] 3 [/SUP], Alex Pelletier[SUP] 1 [/SUP], Martin A Rossotti[SUP] 3 [/SUP], Yuneivy Cepero-Donates[SUP] 1 [/SUP], Jacqueline Slinn[SUP] 3 [/SUP], Patrick Salois[SUP] 1 [/SUP], Anh Tran[SUP] 3 4 [/SUP], Melissa Hewitt[SUP] 3 [/SUP], Alvaro Yogi[SUP] 3 [/SUP], Nazanin Rohani[SUP] 1 [/SUP], Brian Cass[SUP] 1 [/SUP], Anne E G Lenferink[SUP] 1 [/SUP], Jamshid Tanha[SUP] 3 4 5 [/SUP], Binbing Ling[SUP] 3 [/SUP], Etienne Lessard[SUP] 1 [/SUP], Laurence Delafosse[SUP] 1 [/SUP], Jagdeep K Sandhu[SUP] 3 [/SUP], Danica Stanimirovic[SUP] 3 [/SUP]
Affiliations
- PMID: 41870123
- DOI: 10.1128/aac.00024-26
Severe acute respiratory syndrome coronaviruses use the ACE2 receptor for viral entry while downregulating its activity, potentially leading to hypertension and major organ injuries. Dual-action technologies based on soluble ACE2 aimed to neutralize the virus while restoring ACE2's normal enzymatic activity. Here, we describe a novel general molecular design, VHH[SUB]Spike[/SUB]-ACE2[SUB]ECD[/SUB]-VHH[SUB]Albumin[/SUB], in the toolbox of ACE2-centric therapeutic modalities. The optimized nanobody module VHH[SUB]Spike[/SUB] afforded strong pan-specific binding against the entire sarbecoviral clade. This correlated with potent in vitro neutralization of pseudotyped virus variants of concern, with IC[SUB]50[/SUB] values in the picomolar range. Exogenous enzymatic activity was provided by the ACE2[SUB]ECD[/SUB] module, which also contributed binding avidity via intrinsic homodimerization. Persistence of enzymatic activity in circulation was increased in vivo via the nanobody module VHH[SUB]Albumin[/SUB] optimized for serum albumin binding. Single-dose therapeutic administration of lead compound 72opt-ACE2-R28 demonstrated virus neutralization in lungs of hamsters at day 5 post-infection with SARS-CoV-2. In hypertensive mice maintained under continuous injection of angiotensin II, a single dose of 72opt-ACE2-R28 normalized systolic blood pressure, maintaining a 30 mmHg reduction after 24 h. Overall, encouraging coronavirus neutralization and hypertension reduction showed magnitudes and timeframes appropriate for treatment of typical acute infections. We discuss molecular bases of interactions with coronavirus spike protein molecules and future scale-up manufacturability toward clinical development of this modular design scaffold with high potential against emerging SARS-CoV-2 variants.
Keywords: ACE2 enzyme activity; COVID-19; albumin binding; blood pressure reduction; single-domain antibody; spike protein; virus neutralization.