Discovery and Evaluation of Entry Inhibitors for SARS-CoV-2 and Its Emerging Variants

Arpan Acharya, Kabita Pandey, Michellie Thurman, Elizabeth Klug, Jay Trivedi, Kalicharan Sharma, Christian L. Lorson, Kamal Singh, Siddappa N. Byrareddy

Research output: Contribution to journalArticlepeer-review

26 Scopus citations


The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the coronavirus disease 19 (COVID-19) pandemic. Despite unprecedented research and developmental efforts, SARS-CoV-2-specific antivirals are still unavailable for the treatment of COVID-19. In most instances, SARS-CoV-2 infection initiates with the binding of Spike glycoprotein to the host cell ACE2 receptor. Utilizing the crystal structure of the ACE2/Spike receptor-binding domain (S-RBD) complex (PDB file 6M0J) in a computer-aided drug design approach, we identified and validated five potential inhibitors of S-RBD and ACE-2 interaction. Two of the five compounds, MU-UNMC-1 and MU-UNMC-2, blocked the entry of pseudovirus particles expressing SARS-CoV-2 Spike glycoprotein. In live SARS-CoV-2 infection assays, both compounds showed antiviral activity with IC50 values in the micromolar range (MU-UNMC-1: IC50 = 0.67 mM and MU-UNMC-2: IC50 = 1.72 mM) in human bronchial epithelial cells. Furthermore, MU-UNMC-1 and MU-UNMC-2 effectively blocked the replication of rapidly transmitting variants of concern: South African variant B.1.351 (IC50 = 9.27 and 3.00 mM) and Scotland variant B.1.222 (IC50 = 2.64 and 1.39 mM), respectively. Following these assays, we conducted “induced-fit (flexible) docking” to understand the binding mode of MU-UNMC-1/MU-UNMC-2 at the S-RBD/ ACE2 interface. Our data showed that mutation N501Y (present in B.1.351 variant) alters the binding mode of MU-UNMC-2 such that it is partially exposed to the solvent and has reduced polar contacts. Finally, MU-UNMC-2 displayed high synergy with remdesivir, the only approved drug for treating hospitalized COVID-19 patients.

Original languageEnglish (US)
Article numbere01437-21
JournalJournal of virology
Issue number24
StatePublished - Nov 2021

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology


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