Enantioselective Inhibition of Human Papillomavirus L1 Pentamer Formation by Chiral‐Proline Modified Calix[4]arenes: Targeting the Protein Interface. Issue 19 (29th November 2016)

• Record Type: Journal Article
• Authors: Fu, Ding‐Yi; Lu, Tong; Liu, Yu‐Xue; Li, Fei; Ogden, Mark I.; Wang, Ye; Wu, Yuqing; Mocerino, Mauro
• Is Part Of: ChemistrySelect. Volume 1:Issue 19(2016)
• Page Start: 6243
• Page End: 6249
• Publication Date: 2016-11-29
• Subjects: calixarenes -- enantioselective -- HPV -- inhibitors -- L1 pentamer; Chemistry -- Periodicals; 540.5
• DOI: 10.1002/slct.201601467
• Languages: English
• ISSNs: 2365-6549

Abstract

Abstract: Although current human papillomavirus (HPV) vaccines can protect well against infection, they are effective only for a limited number of subtypes. Coupled with the dilemma that no efficient prescription is currently clinically available for therapy, there is an urgent need to develop new anti‐HPV agents. In the present study l ‐ and d ‐Proline modified calix[4]arenes (Pro‐C4 A) were investigated to determine any differences in their effect on the assembly of HPV 16 L1 pentamer (L1‐p). The mechanism of action using model peptides was investigated by Matrix‐Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI‐TOF‐MS) and Nuclear Magnetic Resonance (NMR) and revealed that the binding was targeting the basic residues at L1 interface. This was also well supported by the trypsin digestion experiments and molecular simulations performed on the full‐length L1. The large energy and morphology differences revealed by molecular simulations explain the binding disparity of l ‐ and d ‐Pro‐C4 A to L1, and consequently the selective inhibition of them on L1‐p formation. The present study opens a way to develop enantioselective and cost‐effective inhibitors for L1‐p formation, which might be used as a new kind of anti‐HPV agent and could be extended to other viruses based on similar mechanisms. Abstract : Chiral proline‐modified calix[4]arenes exhibit large enantioselective inhibition of the assembly of human papillomavirus 16 L1 pentamer, targeting the basic residues at the interface. The binding sites were determined by MALDI‐TOF‐MS and NMR, and confirmed by trypsin digestion experiments and molecular docking calculations. This study opens a way to develop enantioselective and cost‐effective inhibitors for HPV L1 pentamer formation, which might be used as a new kind of anti‐HPV agents and could be extended to other viruses based on the identical mechanism.