Peptides in the treatment of AIDS

Abstract

Fusion of HIV-1 and target cells is mediated by the envelope protein gp41 that undergoes a series of conformational changes during the process of infection. Knowledge of the structural biology of gp41 allows the design of potent peptide inhibitors that prevent the virus from entering lymphocytes and macrophages. The design of such inhibitors is the subject of this review.

Figure 1

The life-cycle of HIV-1. The virus attaches to its target cell and subsequent to membrane fusion the RNA of the virus is reverse transcribed to DNA which is integrated into the cell’s genome. During it’s virulent phase the viral DNA is transcribed back to RNA which codes for various proteins required for virion assembly. Drugs can inhibit various events in the life cycle. The focus of the review is peptides that inhibit fusion to the target cell. Figure from http://www.wiley.com/legacy/college/boyer/0470003790/cutting_edge/aids_therapies/hiv_lifecycle.gif

Figure 2

Schematic representation of HIV-1 gp41. The abbreviations represent the fusion peptide (FP); the fusion peptide proximal domain (FPPR); the N-terminal helical region (N-HR), the immunodominant loop region, the C-terminal helical region (C-HR), the membrane proximal region (MPER) and the transmembrane region (TM). The protein is numbered according to the HXB2 HIV-1 strain. The figure was adapted from [23].

Figure 3

Mechanism of action of HIV-1 entry inhibitors. Panel A illustrates the involvement of gp41 in the fusion of the cell and viral membranes and the interference of peptide fusion inhibitors with this event. The inhibitors are believed to prevent formation of the 6-helix hairpin bundle necessary for juxtaposing the cell and viral membranes. C-HR peptides like T-20 bind to the N-HR trimeric core and N-peptides form a trimer which binds to the C-HR helix forming heterocomplexes that are defective in fusion. Panel B Schematic helical wheel diagram used in the design of C-peptides with increased helicity and water solubility. The positions that pack against the N-trimeric core (indicated in yellow) are less favored for replacement than those facing away (indicated in blue). Panel C. 5- Helix inhibitor. The hetero bundle lacks one C-peptide and thus provides a binding pocket for the C-HR peptide of gp41. Adapted from [13,38].

Figure 4

X-ray structure of the gp41 6-helix bundle. The bundle was formed from synthetic N36 and C34 peptides (see Table 1). Panel A shows an end view of the 6-HB with the C-peptides in grey and the trimeric core in green. Panel B is a side view illustrating the trimeric N-core interacting with the C-peptides. The pocket binding domain (PDB; WMEWDREI) residues Trp, Trp and Ile of C34 are shown explicitly. These interact with the hydrophobic pocket of the N-trimeric core. The model was built using coordinates from the PDB 1AIK.

Figure 5

Docking of C34 into the N-trimeric core was used to choose residues for replacement by D-residues. The side chains indicated in red face away from the core and can be replaced with amino acids of opposite chirality. The docking energies provide additional guidance for positions that do not contribute to the binding affinity. Based on this structure C34M3 had D-residues inserted at positions 2, 27 and 31 and had potency comparable to C34 but was more soluble and more stable to protease digestion. Figure from [46].