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Helical Poly(arginine) Mimics with Superior Cell-Penetrating and Molecular Transporting Properties.

ABSTRACT: Poly(arginine) mimics bearing long hydrophobic side chains adopt stable helical conformation and exhibit helix-related cell-penetrating properties. Elongating polypeptide backbone length and increasing side chain hydrophobicity further increase the helicities of poly(arginine) mimics. They show superior cell membrane permeability up to two orders of magnitude higher than that of HIV-TAT peptide and excellent DNA and siRNA delivery efficiencies in various mammalian cells.

SUBMITTER: Tang H

PROVIDER: S-EPMC4232443 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Helical Poly(arginine) Mimics with Superior Cell-Penetrating and Molecular Transporting Properties.

Tang Haoyu H Tang Haoyu H Yin Lichen L Kim Kyung Hoon KH Cheng Jianjun J

Chemical science 20131001 10

Poly(arginine) mimics bearing long hydrophobic side chains adopt stable helical conformation and exhibit helix-related cell-penetrating properties. Elongating polypeptide backbone length and increasing side chain hydrophobicity further increase the helicities of poly(arginine) mimics. They show superior cell membrane permeability up to two orders of magnitude higher than that of HIV-TAT peptide and excellent DNA and siRNA delivery efficiencies in various mammalian cells. ...[more]

PMID: 25400902

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Project description:The capsid domain of the human immunodeficiency virus type 1 (HIV-1) Gag polyprotein is a critical determinant of virus assembly, and is therefore a potential target for developing drugs for AIDS therapy. Recently, a 12-mer alpha-helical peptide (CAI) was reported to disrupt immature- and mature-like capsid particle assembly in vitro; however, it failed to inhibit HIV-1 in cell culture due to its inability to penetrate cells. The same group reported the X-ray crystal structure of CAI in complex with the C-terminal domain of capsid (C-CA) at a resolution of 1.7 A. Using this structural information, we have utilized a structure-based rational design approach to stabilize the alpha-helical structure of CAI and convert it to a cell-penetrating peptide (CPP). The modified peptide (NYAD-1) showed enhanced alpha-helicity. Experiments with laser scanning confocal microscopy indicated that NYAD-1 penetrated cells and colocalized with the Gag polyprotein during its trafficking to the plasma membrane where virus assembly takes place. NYAD-1 disrupted the assembly of both immature- and mature-like virus particles in cell-free and cell-based in vitro systems. NMR chemical shift perturbation analysis mapped the binding site of NYAD-1 to residues 169-191 of the C-terminal domain of HIV-1 capsid encompassing the hydrophobic cavity and the critical dimerization domain with an improved binding affinity over CAI. Furthermore, experimental data indicate that NYAD-1 most likely targets capsid at a post-entry stage. Most significantly, NYAD-1 inhibited a large panel of HIV-1 isolates in cell culture at low micromolar potency. Our study demonstrates how a structure-based rational design strategy can be used to convert a cell-impermeable peptide to a cell-permeable peptide that displays activity in cell-based assays without compromising its mechanism of action. This proof-of-concept cell-penetrating peptide may aid validation of capsid as an anti-HIV-1 drug target and may help in designing peptidomimetics and small molecule drugs targeted to this protein.

Dataset Information

Helical Poly(arginine) Mimics with Superior Cell-Penetrating and Molecular Transporting Properties.

Publications

Helical Poly(arginine) Mimics with Superior Cell-Penetrating and Molecular Transporting Properties.

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