Enfuvirtide (ENF), the first approved fusion inhibitor (FI) for HIV, is a 36-aa peptide that acts by binding to the heptad repeat 1 (HR1) region of gp41 and preventing the interaction of the HR1 and HR2 domains, which is required for virus-cell fusion. Treatmentacquired resistance to ENF highlights the need to create FI therapeutics with activity against ENF-resistant viruses and improved durability. Using rational design, we have made a series of oligomeric HR2 peptides with increased helical structure and with exceptionally high HR1/HR2 bundle stability. The engineered peptides are found to be as much as 3,600-fold more active than ENF against viruses that are resistant to the HR2 peptides ENF, T-1249, or T-651. Passaging experiments using one of these peptides could not generate virus with decreased sensitivity, even after >70 days in culture, suggesting superior durability as compared with ENF. In addition, the pharmacokinetic properties of the engineered peptides were improved up to 100-fold. The potent antiviral activity against resistant viruses, the difficulty in generating resistant virus, and the extended half-life in vivo make this class of fusion inhibitor peptide attractive for further development.coiled coil ͉ gp41 HIV-1 ͉ viral entry ͉ drug design

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Abstract:The synthesis and properties of a number of functionalized calix[4]pyrroles are described. To date, two generalized preparative approaches have been pursued. The first involves modifying the basic pyrrole-plus-ketone synthesis of calix[4]pyrrole by using modified precursors or by co-condensing more than one ketone with pyrrole. The second approach relies on the reaction of a pre-formed calix[4]pyrrole with an electrophile. In both cases, the resulting species can be subject to further manipulation. In this way a range of structures, including ones bearing ancillary recognition subunits, electro-or photochemical reporter groups, and/or water solubilizing substituents may be obtained. Solid supports bearing calix[4]pyrroles may also be produced in this way.

The radiation sensitizer gadolinium(III) texaphyrin 2 (XYTRIN; PCI-0120; Gd−Tex2+) and several other water soluble metallotexaphyrin complexes were prepared and studied using pulse radiolysis. All of the metallotexaphyrins were found to react with solvated electrons and hydroxyl radicals, yielding the corresponding one-electron reduced and oxidized metallotexaphyrins, respectively. The rates of the reduction processes range from 3.7 × 1010 to 6.8 × 1010 M-1 s-1 (±10%), while those involving oxidation range from 2.5 × 109 to 7.4 × 109 M-1 s-1 (±10%). The spectral characteristics of the transformed metallotexaphyrins produced by these reactions, e.g., a broad absorption band with a λmax centered around 830 nm, are consistent with ligand-centered redox processes. Reaction of the metallotexaphyrins with solvated electrons affords species which exhibit metal dependent behavior. In the absence of hydroxyl radicals, the decay of the reduced metallotexaphyrins produced by reaction with electrons involves an initial protonation event followed by either a dimerization process or a disproportionation step. These latter transformations are followed by a second protonation event.