%0 Journal Article
%T Infection by CXCR4-Tropic Human Immunodeficiency Virus Type 1 Is Inhibited by the Cationic Cell-Penetrating Peptide Derived from HIV-1 Tat
%A Shawn Keogan
%A Shendra Passic
%A Fred C. Krebs
%J International Journal of Peptides
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/349427
%X Cell-penetrating peptides (CPP), which are short peptides that are capable of crossing the plasma membrane of a living cell, are under development as delivery vehicles for therapeutic agents that cannot themselves enter the cell. One well-studied CPP is the 10-amino acid peptide derived from the human immunodeficiency virus type 1 (HIV-1) Tat protein. In experiments to test the hypothesis that multiple cationic amino acids within Tat peptide confer antiviral activity against HIV-1, introduction of Tat peptide resulted in concentration-dependent inhibition of HIV-1 IIIB infection. Using Tat peptide variants containing arginine substitutions for two nonionic residues and two lysine residues, HIV-1 inhibition experiments demonstrated a direct relationship between cationic charge and antiviral potency. These studies of Tat peptide as an antiviral agent raise new questions about the role of Tat in HIV-1 replication and provide a starting point for the development of CPPs as novel HIV-1 inhibitors. 1. Introduction Cell penetrating peptides (CPP) are short peptides that can efficiently cross the plasma membrane, which is otherwise a formidable barrier to many extracellular molecules [1¨C3]. CPPs are capable of not only traversing the cell membrane, but also serving as a vehicle for transporting a variety of cargos, including nucleic acids, polymers, nanoparticles, and drugs that cannot otherwise gain entry to the cell [3]. Although the functions of various CPPs have been repeatedly verified in a variety of cells and conditions, the mechanism of CPP uptake is not yet fully understood and may involve energy-dependent and -independent mechanisms [4]. Of the numerous peptides shown to have cell penetrating properties, a 10-amino acid (aa) peptide derived from the human immunodeficiency virus type 1 (HIV-1) Tat protein has been well studied as an effective CPP and an attractive drug delivery agent [5]. The Tat peptide has received particular emphasis as a CPP due to its simplicity and capacity for modification to suit the delivery context or cargo [5, 6]. The core peptide is a 10-aa sequence comprised of six arginine and two lysine residues, as well as two non-ionic amino acids (Table 1). However, numerous Tat peptides of varied lengths and terminal sequences have been investigated with the goals of modifying activity or attaching different cargo [6]. A multitude of studies have determined that the activity of the Tat peptide as a CPP involves interactions with the cellular membrane and cytoskeleton [7], and is influenced by numerous variables related to the
%U http://www.hindawi.com/journals/ijpep/2012/349427/