The hepatitis C virus (HCV) is a causal agent of chronic liver infection, cirrhosis, and hepatocellular carcinoma infecting more than 170 million people. CD81 is a receptor for HCV envelope glycoprotein E2. Although the binding of HCV-E2 with CD81 is well documented the role of this interaction in the viral life cycle remains unclear. Host specificity and mutagenesis studies suggest that the helix D region of CD81 mediates binding to HCV-E2. Structural analysis of CD81 has enabled the synthesis of small molecules designed to mimic the space and hydrophobic features of the solvent-exposed face on helix D. Utilizing a novel bis-imidazole scaffold a series of over 100 compounds has been synthesized. Seven related, imidazole-based compounds were identified that inhibit binding of HCV-E2 to CD81. The inhibitory compounds have no short-term effect on cellular expression of CD81 or other tetraspanins, do not disrupt CD81 associations with other cell surface proteins, and bind reversibly to HCV-E2. These results provide an important proof of concept that CD81-based mimics can disrupt binding of HCV-E2 to CD81.
Peptides containing the sequence Arg-Gly-Asp antagonize binding of fibrinogen to its platelet GPIIb/IIIa receptor, thereby inhibiting platelet aggregation. Incorporation of the sequence into cyclic pentapeptide disulfides has been reported to yield effective antagonists. The conformations in solution of two such antagonists, (2-mercaptobenzoy1)-Na-methylArgGly-Asp-2-mercaptoanilide cyclic disulfide (1) and Ac-Cys-Na-methylArg-Gly-A~p-Pen-NH~ cyclic disulfide (2), have been studied using a constrained distance geometry search procedure in conjunction with proton NMR data, and a structure of 1 has been determined from single-crystal X-ray diffraction data. NMR spectra of the cyclic diaryl disulfide 1 at 203 K in methanol show two slowly exchanging conformations. The Arg-Gly-Asp region of the major form is characterized, inter alia, by an extended Gly residue flanked by an Na-methylArg residue in a conformation roughly consistent with the i + 2 position of a &turn and an Asp residue in a C7 like conformation. In the minor component, the Asp residue is near the aR conformation. The bamer to exchange between the two forms is estimated at 11 kcal/mol. NMR data and analysis of the constrained distance geometry search results suggest that, at room temperature in dimethyl sulfoxide-sulfolane, the dominant conformation of the Arg-Gly-Asp regions of both 1 and 2 is like that in the major component of 1 at 203 K. (2-Mercaptobenzoy1)-Na-methylArg-Gly-Asp-2-mercaptoanilide cyclic disulfide (1) was crystallized from aqueous ethanol as a solvated nitrate salt in a cell of dimensions a = 27.919 (16) A, b = 7.552 (3) A, c = 16.3131 (10) A, and j 3 = 108.79 (5)' with four formula units in space group C2. The structure was solved by direct methods and refined to R = 0.057 for 2869 observations (I 2 340). The crystal structure of 1 and the most probable conformation of its minor form in solution agree closely.
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