Electrostatically constrained α-helical peptide inhibits replication of HIV-1 resistant to enfuvirtide
| Autor: | Hiroki Nishikawa, Nobutaka Fujii, Shota Nakamura, Tadayasu Ohkubo, Keiko Kajiwara, Kazuki Izumi, Masao Matsuoka, Yasuko Sakagami, Yuji Kobayashi, Saori Ito, Akira Otaka, Shinya Oishi, Eiichi Kodama |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Inhibitor
Enfuvirtide Molecular Sequence Data Static Electricity Peptide Biology Virus Replication Gp41 Biochemistry Protein Structure Secondary Structure-Activity Relationship Protein structure HIV Fusion Inhibitors Drug Resistance Viral medicine Animals Humans Amino Acid Sequence Fusion Peptide sequence chemistry.chemical_classification Circular Dichroism HIV Lipid bilayer fusion Cell Biology HIV Envelope Protein gp41 Peptide Fragments Amino acid Heptad repeat chemistry Drug Design HIV-1 Cattle α-Helix Peptides HeLa Cells Protein Binding medicine.drug |
| Zdroj: | The International Journal of Biochemistry & Cell Biology. 41:891-899 |
| ISSN: | 1357-2725 |
| DOI: | 10.1016/j.biocel.2008.08.039 |
| Popis: | Alpha-helical peptides, such as T-20 (enfuvirtide) and C34, derived from the gp41 carboxyl-terminal heptad repeat (C-HR) of HIV-1, inhibit membrane fusion of HIV-1 and the target cells. Although T-20 effectively suppresses the replication of multi-drug resistant HIV variants both in vitro and in vivo, prolonged therapy with T-20 induces emergence of T-20 resistant variants. In order to suppress the emergence of such resistant variants, we introduced charged and hydrophilic amino acids, glutamic acid (E) and lysine (K), at the solvent accessible site of C34. In particular, the modified peptide, SC34EK, demonstrates remarkably potent inhibition of membrane fusion by the resistant HIV-1 variants as well as wild-type viruses. The activity was specific to HIV-1 and little influenced by serum components. We found a strong correlation between the anti-HIV-1 activities of these peptides and the thermostabilities of the 6-helix bundles that are formed with these peptides. We also obtained the crystal structure of SC34EK in complex with a 36 amino acid sequence (N36) comprising the amino-terminal heptad repeat of HIV-1. The EK substitutions in the sequence of SC34EK were directed toward the solvent and generated an electrostatic potential, which may result in enhanced alpha-helicity of the peptide inhibitor. The 6-helix bundle complex of SC34EK with N36 appears to be structurally similar to that of C34 and N36. Our approach to enhancing alpha-helicity of the peptide inhibitor may enable future design of highly effective and specific HIV-1 inhibitors. |
| Databáze: | OpenAIRE |
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