Journal of medicinal and pharmaceutical chemistry 2009-07-23

The role of amphiphilicity and negative charge in glycoprotein 41 interactions in the hydrophobic pocket.

Miriam Gochin, Lifeng Cai

Index: J. Med. Chem. 52 , 4338-44, (2009)

Full Text: HTML

Abstract

The hydrophobic pocket within the coiled coil domain of HIV-1 gp41 is considered to be a hot-spot suitable for small molecule intervention of fusion, although so far it has yielded only microM inhibitors. Previous peptide studies have identified specific hydrophobic interactions and a Lys-Asp salt bridge as contributing to binding affinity in the pocket. Negative charge appears to be critical for activity of small molecules. We have examined the role of charge and amphiphilic character in the interaction by studying a series of short pocket binding peptides differing in charge, helical content, and in the presence or absence of the Lys-Asp salt bridge, and a series of fatty acid salts with varying charge and hydrocarbon length. Quantitative binding analysis revealed that long-range electrostatic forces and a greasy nonspecific hydrophobic interaction were sufficient for microM potency. The results suggest that an extended interaction site may be necessary for higher potency. We examined a region of the coiled coil immediately C-terminal to the pocket and found that specific salt bridge and hydrogen bond networks may reside in this region. Negatively charged groups extended toward or beyond the C-terminus of the pocket could therefore result in improved low molecular weight fusion inhibitors.


Related Compounds

Related Articles:

Salicylic acid signaling controls the maturation and localization of the arabidopsis defense protein ACCELERATED CELL DEATH6.

2014-08-01

[Mol. Plant 7(8) , 1365-83, (2014)]

Genetic and pharmacologic inhibition of eIF4E reduces breast cancer cell migration, invasion, and metastasis.

2015-03-15

[Cancer Res. 75(6) , 1102-12, (2015)]

ZEB2 drives immature T-cell lymphoblastic leukaemia development via enhanced tumour-initiating potential and IL-7 receptor signalling.

2015-01-01

[Nat. Commun. 6 , 5794, (2015)]

Neuropeptide Y in the noradrenergic neurones induces obesity and inhibits sympathetic tone in mice.

2015-04-01

[Acta Physiol. (Oxf.) 213(4) , 902-19, (2015)]

Proteasome-mediated degradation of FRIGIDA modulates flowering time in Arabidopsis during vernalization.

2014-12-01

[Plant Cell 26(12) , 4763-81, (2015)]

More Articles...