Computationally Designed ACE2 Decoy Receptor Binds SARS-CoV-2 Spike (S) Protein with Tight Nanomolar Affinity.
Brandon HavranekKui K ChanAustin WuErik ProckoShahidul M IslamPublished in: Journal of chemical information and modeling (2021)
Even with the availability of vaccines, therapeutic options for COVID-19 still remain highly desirable, especially in hospitalized patients with moderate or severe disease. Soluble ACE2 (sACE2) is a promising therapeutic candidate that neutralizes SARS CoV-2 infection by acting as a decoy. Using computational mutagenesis, we designed a number of sACE2 derivatives carrying three to four mutations. The top-predicted sACE2 decoy based on the in silico mutagenesis scan was subjected to molecular dynamics and free-energy calculations for further validation. After illuminating the mechanism of increased binding for our designed sACE2 derivative, the design was verified experimentally by flow cytometry and BLI-binding experiments. The computationally designed sACE2 decoy (ACE2-FFWF) bound the receptor-binding domain of SARS-CoV-2 tightly with low nanomolar affinity and ninefold affinity enhancement over the wild type. Furthermore, cell surface expression was slightly greater than wild-type ACE2, suggesting that the design is well-folded and stable. Having an arsenal of high-affinity sACE2 derivatives will help to buffer against the emergence of SARS CoV-2 variants. Here, we show that computational methods have become sufficiently accurate for the design of therapeutics for current and future viral pandemics.
Keyphrases
- sars cov
- wild type
- molecular dynamics
- respiratory syndrome coronavirus
- binding protein
- angiotensin converting enzyme
- flow cytometry
- angiotensin ii
- density functional theory
- cell surface
- crispr cas
- dna binding
- poor prognosis
- blood brain barrier
- molecular dynamics simulations
- coronavirus disease
- magnetic resonance imaging
- capillary electrophoresis
- magnetic resonance
- early onset
- gene expression
- high resolution
- molecular docking
- mass spectrometry
- long non coding rna
- genome wide
- transcription factor
- structure activity relationship
- protein protein