The receptor-binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2s pike (S) protein playsacentral role in mediating the first step of virus infection to cause disease:v irus binding to angiotensin-converting enzyme 2( ACE2) receptors on human host cells.T herefore, S/RBD is an ideal target for blocking and neutralization therapies to prevent and treat coronavirus disease 2019 (COVID-19). Using at arget-based selection approach, we developed oligonucleotide aptamers containing ac onserved sequence motif that specifically targets S/RBD.S ynthetic aptamers had high binding affinity for S/RBD-coated virus mimics (K D % 7nM) and also blocked interaction of S/RBD with ACE2 receptors (IC 50 % 5nM). Importantly,a ptamers were able to neutralizeSprotein-expressing viral particles and prevent host cell infection, suggesting apromising COVID-19 therapys trategy.