Two series of redox-active, iron−sulfur core dendrimers of the general structure (nBu4N)2[Fe4S4(S-Dend)4] (Dend = dendrons of generations 1 through 4) were prepared. Heterogeneous electron-transfer rate constants indicated that the rigid series of dendrimers were more effective at attenuating the rate of electron transfer than were the flexible series of dendrimers. These results were rationalized using computationally derived models which indicated an offset and mobile iron−sulfur core in the flexible series of molecules and a more central and relatively immobile iron−sulfur core in the rigid series of molecules. Further consideration of these data indicated that, while the dendrimers containing rigid ligands had better encapsulated redox cores for a given molecular weight, these molecules had higher electron-transfer rates for a given molecular radius.

No abstract

The longitudinal relaxation time constants (T 1) of the protons in a series of dendrimers that alternatively had paramagnetic ([Fe4S4(SR)4]2-, R = dendron) and diamagnetic (tetraphenylmethane) cores were compared. The T 1 values of the phenyl and benzyl protons in the paramagnetic core dendrimers were attenuated compared to those of analogous protons in the diamagnetic core dendrimers. This observation indicated that protons in each set of topologically different repeat units (generation) of the dendrimer approach the core of the molecule closely in space. This conclusion is consistent with the computed radial density distributions of the different generations calculated from molecular dynamics simulations. In addition, by comparing T 1 values of protons at two slightly different temperatures, the terminal groups in both sets of dendrimers were concluded to be, on average, more mobile than the other generations within the dendrimers. This conclusion is consistent with the computed mean square displacement correlation functions for the different generations also calculated from molecular dynamics simulations.

Zika virus (ZIKV) is an emerging human pathogen that is spreading rapidly through the Americas and has been linked to the development of microcephaly and to a dramatically increased number of Guillain-Barré syndrome cases. Currently, no vaccine or therapeutic options for the prevention or treatment of ZIKV infections exist. In the study described in this report, we expressed, purified, and characterized full-length nonstructural protein 5 (NS5) and the NS5 polymerase domain (NS5pol) of ZIKV RNA-dependent RNA polymerase. Using purified NS5, we developed an in vitro nonradioactive primer extension assay employing a fluorescently labeled primertemplate pair. Both purified NS5 and NS5pol can carry out in vitro RNA-dependent RNA synthesis in this assay. Our results show that Mn 2ϩ is required for enzymatic activity, while Mg 2ϩ is not. We found that ZIKV NS5 can utilize single-stranded DNA but not double-stranded DNA as a template or a primer to synthesize RNA. The assay was used to compare the efficiency of incorporation of analog 5=-triphosphates by the ZIKV polymerase and to calculate their discrimination versus that of natural ribonucleotide triphosphates (rNTPs). The 50% inhibitory concentrations for analog rNTPs were determined in an alternative nonradioactive coupled-enzyme assay. We determined that, in general, 2=-C-methyl-and 2=-C-ethynyl-substituted analog 5=-triphosphates were efficiently incorporated by the ZIKV polymerase and were also efficient chain terminators. Derivatives of these molecules may serve as potential antiviral compounds to be developed to combat ZIKV infection. This report provides the first characterization of ZIKV polymerase and demonstrates the utility of in vitro polymerase assays in the identification of potential ZIKV inhibitors.

No abstract