Quinolizidines as Novel SARS-CoV-2 Entry Inhibitors

• Published in: International journal of molecular sciences Vol. 23; no. 17; p. 9659
• Main Authors: Huang, Li, Zhu, Lei, Xie, Hua, Goodwin, Jeffery Shawn, Rana, Tanu, Xie, Lan, Chen, Chin-Ho
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 25.08.2022; MDPI
• Subjects: Antibodies; Antiviral drugs; Coronaviruses; COVID-19 Drug Treatment; COVID-19 vaccines; HIV Fusion Inhibitors; Humans; Infections; Influenza; Mutation; Pandemics; Proteins; Quinolizidines - pharmacology; RNA polymerase; SARS-CoV-2; Severe acute respiratory syndrome coronavirus 2; Virus Internalization; Viruses; aloperine derivatives; SARS-CoV-2 inhibitor; aloperine
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23179659

COVID-19, caused by the highly transmissible severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has rapidly spread and become a pandemic since its outbreak in 2019. We have previously discovered that aloperine is a new privileged scaffold that can be modified to become a specific antiviral compound with markedly improved potency against different viruses, such as the influenza virus. In this study, we have identified a collection of aloperine derivatives that can inhibit the entry of SARS-CoV-2 into host cells. Compound 5 is the most potent tested aloperine derivative that inhibited the entry of SARS-CoV-2 (D614G variant) spike protein-pseudotyped virus with an IC50 of 0.5 µM. The compound was also active against several other SARS-CoV-2 variants including Delta and Omicron. Results of a confocal microscopy study suggest that compound 5 inhibited the viral entry before fusion to the cell or endosomal membrane. The results are consistent with the notion that aloperine is a privileged scaffold that can be used to develop potent anti-SARS-CoV-2 entry inhibitors.