Role of tyrosine M210 in the initial charge separation of reaction centers of Rhodobacter sphaeroides

Femtosecond spectroscopy was used in combination with site-directed mutagenesis to study the influence of tyrosine M210 (YM210) on the primary electron transfer in the reaction center of Rhodobacter sphaeroides. The exchange of YM210 to phenylalanine caused the time constant of primary electron transfer to increase from 3.5 f 0.4 ps to 16 f 6 ps while the exchange to leucine increased the time constant even more to 22 f 8 ps. The results suggest that tyrosine M210 is important for the fast rate of the primary electron transfer

Growth, microstructure, and failure of crazes in glassy polymers

We report on an extensive study of craze formation in glassy polymers. Molecular dynamics simulations of a coarse-grained bead-spring model were employed to investigate the molecular level processes during craze nucleation, widening, and breakdown for a wide range of temperature, polymer chain length $N$, entanglement length $N_e$ and strength of adhesive interactions between polymer chains. Craze widening proceeds via a fibril-drawing process at constant drawing stress. The extension ratio is determined by the entanglement length, and the characteristic length of stretched chain segments in the polymer craze is $N_e/3$. In the craze, tension is mostly carried by the covalent backbone bonds, and the force distribution develops an exponential tail at large tensile forces. The failure mode of crazes changes from disentanglement to scission for $N/N_e\sim 10$, and breakdown through scission is governed by large stress fluctuations. The simulations also reveal inconsistencies with previous theoretical models of craze widening that were based on continuum level hydrodynamics

Ferrous iron-dependent drug delivery enables controlled and selective release of therapeutic agents in vivo

The precise targeting of cytotoxic agents to specific cell types or cellular compartments is of significant interest in medicine, with particular relevance for infectious diseases and cancer. Here, we describe a method to exploit aberrant levels of mobile ferrous iron (Fe(II)) for selective drug delivery in vivo. This approach makes use of a 1,2,4-trioxolane moiety, which serves as an Fe(II)-sensitive "trigger," making drug release contingent on Fe(II)-promoted trioxolane fragmentation. We demonstrate in vivo validation of this approach with the Plasmodium berghei model of murine malaria. Malaria parasites produce high concentrations of mobile ferrous iron as a consequence of their catabolism of host hemoglobin in the infected erythrocyte. Using activity-based probes, we successfully demonstrate the Fe(II)-dependent and parasite-selective delivery of a potent dipeptidyl aminopeptidase inhibitor. We find that delivery of the compound in its Fe(II)-targeted form leads to more sustained target inhibition with greatly reduced off-target inhibition of mammalian cathepsins. This selective drug delivery translates into improved efficacy and tolerability. These findings demonstrate the utility of a purely chemical means to achieve selective drug targeting in vivo. This approach may find useful application in parasitic infections and more broadly in any disease state characterized by aberrant production of reactive ferrous iron

Ferrous iron-dependent drug delivery enables controlled and selective release of therapeutic agents in vivo

The precise targeting of cytotoxic agents to specific cell types or cellular compartments is of significant interest in medicine, with particular relevance for infectious diseases and cancer. Here, we describe a method to exploit aberrant levels of mobile ferrous iron (Fe(II)) for selective drug delivery in vivo. This approach makes use of a 1,2,4-trioxolane moiety, which serves as an Fe(II)-sensitive “trigger,” making drug release contingent on Fe(II)-promoted trioxolane fragmentation. We demonstrate in vivo validation of this approach with the Plasmodium berghei model of murine malaria. Malaria parasites produce high concentrations of mobile ferrous iron as a consequence of their catabolism of host hemoglobin in the infected erythrocyte. Using activity-based probes, we successfully demonstrate the Fe(II)-dependent and parasite-selective delivery of a potent dipeptidyl aminopeptidase inhibitor. We find that delivery of the compound in its Fe(II)-targeted form leads to more sustained target inhibition with greatly reduced off-target inhibition of mammalian cathepsins. This selective drug delivery translates into improved efficacy and tolerability. These findings demonstrate the utility of a purely chemical means to achieve selective drug targeting in vivo. This approach may find useful application in parasitic infections and more broadly in any disease state characterized by aberrant production of reactive ferrous iron