Structure-based stabilization of protein-protein interactions (PPIs) is a promising strategy for drug discovery. However, this approach has mainly focused on the stabilization of native PPIs and non-native PPIs have received little consideration. Here, we identified a non-native interaction interface on the 3D dimeric structure of the N-terminal domain of the MERS-CoV nucleocapsid protein (MERS-CoV N-NTD). The interface formed a conserved hydrophobic cavity suitable for targeted drug screening. By considering the hydrophobic complementarity during the virtual screening step, we identified 5-benzyloxygramine as a new N protein PPI orthosteric stabilizer that possesses both antiviral and N-NTD protein-stabilizing activity. X-ray crystallography and small-angle X-ray scattering showed that 5-benzyloxygramine stabilizes the N-NTD dimers through simultaneous hydrophobic interactions to both partners, resulting in abnormal N protein oligomerization that was further confirmed in the cell. This unique approach based on the identification and stabilization of non-native PPIs of N protein could be applied towards drug discovery against CoV diseases.
In Vivo Allergen-Activated Eosinophils Promote Collagen I and Fibronectin Gene Expression in Airway Smooth Muscle Cells via TGF-1 Signaling Pathway in Asthma.
March 12, 2020
Application of untargeted lipidomics based on UHPLC-high resolution tandem MS analysis to profile the lipid metabolic disturbances in the heart of diabetic cardiomyopathy mice.
August 24, 2020
Efficacy of Digital Cognitive Behavioral Therapy for the Treatment of Insomnia Symptoms Among Pregnant Women: A Randomized Clinical Trial.
January 23, 2020
- ACC 2020The American College of Cardiology decided to cancel ACC.20/WCC due to COVID-19, which was scheduled to take place March 28-30 in Chicago. However, ACC.20/WCC Virtual Meeting continues to release cutting edge science and practice changing updates for cardiovascular professionals on demand and free through June 2020.
- ENDO: 2020ENDO 2020 Annual Conference has been canceled due to COVID-19. Here are highlights of emerging data that has still been released. Keep an eye out for ENDO Online 2020, which will take place from June 8 to 22.