RT Journal Article SR Electronic T1 SARS-CoV-2 RBD in vitro evolution follows contagious mutation spread, yet generates an able infection inhibitor JF bioRxiv FD Cold Spring Harbor Laboratory SP 2021.01.06.425392 DO 10.1101/2021.01.06.425392 A1 Zahradník, Jiří A1 Marciano, Shir A1 Shemesh, Maya A1 Zoler, Eyal A1 Chiaravalli, Jeanne A1 Meyer, Björn A1 Dym, Orly A1 Elad, Nadav A1 Schreiber, Gideon YR 2021 UL http://biorxiv.org/content/early/2021/01/08/2021.01.06.425392.abstract AB SARS-CoV-2 is constantly evolving, with more contagious mutations spreading rapidly. Using in vitro evolution to affinity maturate the receptor-binding domain (RBD) of the spike protein towards ACE2, resulted in the more contagious mutations, S477N, E484K, and N501Y to be among the first selected. This includes the British and South-African variants. Plotting the binding affinity to ACE2 of all RBD mutations against their incidence in the population shows a strong correlation between the two. Further in vitro evolution enhancing binding by 600-fold provides guidelines towards potentially new evolving mutations with even higher infectivity. For example, Q498R in combination with N501Y. This said, the high-affinity RBD is also an efficient drug, inhibiting SARS-CoV-2 infection. The 2.9Å Cryo-EM structure of the high-affinity complex, including all rapidly spreading mutations provides structural basis for future drug and vaccine development and for in silico evaluation of known antibodies.Competing Interest StatementThe authors J.Z. and G.S. declare the US Provisional Patent Application No. 63/125,984 (Yeda Ref.: 2020-091).