Design and characterization of human respiratory syncytial virus entry inhibitors. Antivir Ther 2005;10(7):833-40
Date
11/30/2005Pubmed ID
16312179Scopus ID
2-s2.0-27844511949 (requires institutional sign-in at Scopus site) 15 CitationsAbstract
Human respiratory syncytial virus (hRSV) is a pathogen of worldwide health concern. The crucial membrane fusion event during viral entry into host cells involves a 'trimer-of-hairpins' structure that brings the amino (N)- and carboxy (C)-terminal regions of the viral fusion glycoprotein (F protein) into close proximity. Two heptad repeat regions that are highly conserved in the F protein - HR1 (N-terminal) and HR2 (C-terminal) - have an important role in this process. It has been shown that both HR1-and HR2-based peptides can inhibit viral entry. However, these proteins, and the HR1 peptides in particular, are liable to aggregation. We designed three peptides containing multiple copies of alternating HR1 and HR2 sequences denoted 5-Helix, HR121 and HR212, respectively. The 5-Helix, HR121 and HR212 proteins were functionally analogous to single HR1, HR1 and HR2 sequences, respectively. All three proteins were expressed in soluble form and biophysical analysis showed that they exhibited alpha-helical secondary structures. The three proteins were potent fusion inhibitors in vitro, at the micromolar scale, with the HR1 analogues being approximately two times more effective than the HR2 analogue. Our results suggest that these rationally designed protein inhibitors could serve as a new class of anti-hRSV agents.
Author List
Ni L, Zhao L, Qian Y, Zhu J, Jin Z, Chen YW, Tien P, Gao GFAuthor
Jieqing Zhu PhD Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Antiviral AgentsCell Line, Tumor
Cell Membrane
Dose-Response Relationship, Drug
Drug Design
Humans
Membrane Fusion
Peptides
Protein Binding
Respiratory Syncytial Virus Infections
Respiratory Syncytial Virus, Human
Viral Fusion Proteins
