tailieunhanh - Báo cáo y học: "Antiviral activity of a-helical stapled peptides designed from the HIV-1 capsid dimerization domain"

Tuyển tập các báo cáo nghiên cứu về y học được đăng trên tạp chí y học Respiratory Research cung cấp cho các bạn kiến thức về ngành y đề tài: Antiviral activity of a-helical stapled peptides designed from the HIV-1 capsid dimerization domain. | Zhang et al. Retrovirology 2011 8 28 http content 8 1 28 RETR0VIR0L0GY RESEARCH Open Access Antiviral activity of a-helical stapled peptides designed from the HIV-1 capsid dimerization domain 1 11 2 3 4 Hongtao Zhang Francesca Curreli Xihui Zhang Shibani Bhattacharya Abdul A Waheed Alan Cooper David Cowburn5 Eric O Freed3 and Asim K Debnath1 Abstract Background The C-terminal domain CTD of HIV-1 capsid CA like full-length CA forms dimers in solution and CTD dimerization is a major driving force in Gag assembly and maturation. Mutations of the residues at the CTD dimer interface impair virus assembly and render the virus non-infectious. Therefore the CTD represents a potential target for designing anti-HIV-1 drugs. Results Due to the pivotal role of the dimer interface we reasoned that peptides from the a-helical region of the dimer interface might be effective as decoys to prevent CTD dimer formation. However these small peptides do not have any structure in solution and they do not penetrate cells. Therefore we used the hydrocarbon stapling technique to stabilize the a-helical structure and confirmed by confocal microscopy that this modification also made these peptides cell-penetrating. We also confirmed by using isothermal titration calorimetry ITC sedimentation equilibrium and NMR that these peptides indeed disrupt dimer formation. In in vitro assembly assays the peptides inhibited mature-like virus particle formation and specifically inhibited HIV-1 production in cellbased assays. These peptides also showed potent antiviral activity against a large panel of laboratory-adapted and primary isolates including viral strains resistant to inhibitors of reverse transcriptase and protease. Conclusions These preliminary data serve as the foundation for designing small stable a-helical peptides and small-molecule inhibitors targeted against the CTD dimer interface. The observation that relatively weak CA binders such as NYAD-201 and NYAD-202 showed