Design and characterization of human respiratory syncytial virus entry inhibitors

• Published in: Antiviral therapy 2005-01, Vol.10 (7), p.833-840
• Main Authors: LING NI, LINQING ZHAO, YUAN QIAN, JIEQING ZHU, ZHIBO JIN, YU WAI CHEN, PO TIEN, GAO, George F
• Format: Article
• Language: English
• Subjects: Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Biological and medical sciences; Cell Line, Tumor; Cell Membrane - virology; Dose-Response Relationship, Drug; Drug Design; Humans; Medical sciences; Membrane Fusion - drug effects; Peptides - chemistry; Peptides - pharmacology; Pharmacology. Drug treatments; Protein Binding - drug effects; Respiratory Syncytial Virus Infections - prevention & control; Respiratory Syncytial Virus Infections - virology; Respiratory Syncytial Virus, Human - drug effects; Respiratory Syncytial Virus, Human - physiology; Viral Fusion Proteins - antagonists & inhibitors; Viral Fusion Proteins - metabolism
• ISSN: 1359-6535; 2040-2058
• DOI: 10.1177/135965350501000707

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.