De novo design of potent and resilient hACE2 decoys to neutralize SARS-CoV-2

Linsky, Thomas W.; Vergara, Renan; Codina, Nuria; Nelson, Jorgen; Walker, Matthew; Su, Wen; Barnes, Christopher O.; Hsiang, Tien-Ying; Esser-Nobis, Katharina; Yu, Kevin; Reneer, Z. Beau; Hou, Yixuan J.; Priya, Tanu; Mitsumoto, Masaya; Pong, Avery; Lau, Uland Y.; Mason, Marsha L.; Chen, Jerry; Chen, Alex; Berrocal, Tania; Peng, Hong; Clairmont, Nicole S.; Castellanos, Javier; Lin, Yueh‐Chien; Josephson-Day, Anna; Baric, Ralph S.; Fuller, Deborah H.; Walkey, Carl; Ross, Ted M.; Swanson, Richard A.; Björkman, Pamela J.; Gale, Michael; Blancas‐Mejia, Luis M.; Yen, Hui-Ling; Silva, Daniel‐Adriano

doi:10.1126/science.abe0075

Cited by 183 publications

(196 citation statements)

References 67 publications

(51 reference statements)

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“…Overall, the alanine screening analysis confirmed that the 20 interacting residues identified using the full-length trimeric spike protein play key roles in the binding interaction between the spike protein and ACE2. Recently, 35,000 de novo hACE2 decoys were designed and CTC-445.2 was found to tightly bind with the RDB of the trimeric spike protein in four different states (state 1: 1 RBD up, state 2: 2 RBD up, state 3: 1 RBD up and 1 RBD down, and state 4: 2 RBD up and 1 RBD down) (Linsky et al, 2020) which were deposited in the electron microscopy databank and protein data bank, but the structures are not yet available for the public. Eleven residues of the state four trimeric spike protein were determined to interface with CTC-442.2.…”

Section: Binding Free Energy Calculationmentioning

confidence: 99%

Elucidating Interactions Between SARS-CoV-2 Trimeric Spike Protein and ACE2 Using Homology Modeling and Molecular Dynamics Simulations

et al. 2021

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Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19). As of October 21, 2020, more than 41.4 million confirmed cases and 1.1 million deaths have been reported. Thus, it is immensely important to develop drugs and vaccines to combat COVID-19. The spike protein present on the outer surface of the virion plays a major role in viral infection by binding to receptor proteins present on the outer membrane of host cells, triggering membrane fusion and internalization, which enables release of viral ssRNA into the host cell. Understanding the interactions between the SARS-CoV-2 trimeric spike protein and its host cell receptor protein, angiotensin converting enzyme 2 (ACE2), is important for developing drugs and vaccines to prevent and treat COVID-19. Several crystal structures of partial and mutant SARS-CoV-2 spike proteins have been reported; however, an atomistic structure of the wild-type SARS-CoV-2 trimeric spike protein complexed with ACE2 is not yet available. Therefore, in our study, homology modeling was used to build the trimeric form of the spike protein complexed with human ACE2, followed by all-atom molecular dynamics simulations to elucidate interactions at the interface between the spike protein and ACE2. Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) and in silico alanine scanning were employed to characterize the interacting residues at the interface. Twenty interacting residues in the spike protein were identified that are likely to be responsible for tightly binding to ACE2, of which five residues (Val445, Thr478, Gly485, Phe490, and Ser494) were not reported in the crystal structure of the truncated spike protein receptor binding domain (RBD) complexed with ACE2. These data indicate that the interactions between ACE2 and the tertiary structure of the full-length spike protein trimer are different from those between ACE2 and the truncated monomer of the spike protein RBD. These findings could facilitate the development of drugs and vaccines to prevent SARS-CoV-2 infection and combat COVID-19.

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Section: Binding Free Energy Calculationmentioning

confidence: 99%

Elucidating Interactions Between SARS-CoV-2 Trimeric Spike Protein and ACE2 Using Homology Modeling and Molecular Dynamics Simulations

et al. 2021

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“…There have been recent reports on soluble ACE2 proteins that tested their decoy effect in vitro (13)(14)(15)(16)(17)(18)(19)(20). To date, to our knowledge, there is only one report testing soluble ACE2 variants for SARS-CoV-2 infection in an animal model.…”

Section: Discussionmentioning

confidence: 99%

“…In keeping with this concept early in 2020, we hypothesized that soluble ACE2, by acting as a decoy, could be used as a potential therapeutic approach for SARS-CoV-2 infection (12). There have been recent in vitro studies testing decoys for SARS-CoV-2 (13)(14)(15)(16)(17)(18)(19)(20). In vivo studies, however, in suitable animal models, to our knowledge, are lacking.…”

Section: Introductionmentioning

confidence: 99%

A novel soluble ACE2 protein totally protects from lethal disease caused by SARS-CoV-2 infection

Hassler

Wysocki

Gelarden

et al. 2021

Preprint

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Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) uses full-length angiotensin converting enzyme 2 (ACE2), which is membrane bound, as its initial cell contact receptor preceding viral entry. Here we report a human soluble ACE2 variant fused with a 5kD albumin binding domain (ABD) and bridged via a dimerization motif hinge-like 4-cysteine dodecapeptide, which we term ACE2 1-618-DDC-ABD. This protein is enzymatically active, has increased duration of action in vivo conferred by the ABD-tag, and displays 20-30-fold higher binding affinity to the SARS-CoV-2 receptor binding domain than its des-DDC monomeric form (ACE2 1-618-ABD) due to DDC-linked dimerization. ACE2 1-618-DDC-ABD was administered for 3 consecutive days to transgenic k18-hACE2 mice, a model that develops lethal SARS-CoV-2 infection, to evaluate the preclinical preventative/ therapeutic value for COVID-19. Mice treated with ACE2 1-618-DDC-ABD developed a mild to moderate disease for the first few days assessed by a clinical score and modest weight loss. The untreated control animals, by contrast, became severely ill and had to be sacrificed by day 6/7 and lung histology revealed extensive pulmonary alveolar hemorrhage and mononuclear infiltrates. At 6 days, mortality was totally prevented in the treated group, lung histopathology was improved and viral titers markedly reduced. This demonstrates for the first time in vivo the preventative/ therapeutic potential of a novel soluble ACE2 protein in a preclinical animal model.

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“…Recently, peptides mimicking the N-terminal helix of the human ACE2 protein, which contains most of the residues contacting with the S protein-binding site, were shown to block SARS-CoV-2 infection of human pulmonary cells with IC 50 values in the range of 60–800 nM [ 343 ]. Similarly, trimeric ACE2 proteins [ 344 ], decoy ACE2 based proteins [ 345 ] or ACE2 peptides optimized to SARS-CoV-2 S protein-binding regions using protein-engineering methods [ 346 ] potently bound to S protein and inhibited SARS-CoV-2 infection at low nM concentrations in cell lines and in in vivo experiments [ 346 ]. In other studies, fusion proteins consisting of immunoglobulin Fc protein and ACE2 effectively blocked SARS-CoV-2 infection at nM concentrations in HEK-293T cells [ 347 , 348 ].…”

Section: Pharmacology Of Ace2 and Ace2 Related Antiviral Treatmentsmentioning

confidence: 99%

Multifunctional angiotensin converting enzyme 2, the SARS-CoV-2 entry receptor, and critical appraisal of its role in acute lung injury

Öz¹,

Lorke²

2021

Biomedicine & Pharmacotherapy

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De novo design of potent and resilient hACE2 decoys to neutralize SARS-CoV-2

Cited by 183 publications

References 67 publications

Elucidating Interactions Between SARS-CoV-2 Trimeric Spike Protein and ACE2 Using Homology Modeling and Molecular Dynamics Simulations

Elucidating Interactions Between SARS-CoV-2 Trimeric Spike Protein and ACE2 Using Homology Modeling and Molecular Dynamics Simulations

A novel soluble ACE2 protein totally protects from lethal disease caused by SARS-CoV-2 infection

Multifunctional angiotensin converting enzyme 2, the SARS-CoV-2 entry receptor, and critical appraisal of its role in acute lung injury

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