Biophysical Mechanisms Of Action Research Articles

Antivirals acting on viral envelopes via biophysical mechanisms of action

Most antivirals target viral proteins and are specific for only one virus, or viral type. Whereas viral proteins are encoded in the plastic viral genome, virion lipids are not and their rearrangements during fusion are conserved among otherwise unrelated enveloped viruses. Antivirals that inhibit these lipid rearrangements could thus pose a high barrier to resistance and have broad-spectrum activity.Fusion occurs through a hemifusion stalk in which only the outer leaflets are fused and thus curved with a smaller radius for the polar heads than for the hydrophobic tails (negative curvature). Outer leaflets enriched in phospholipids with head groups of larger cross sections than their lipid tails (“inverted cone”) disfavor negative curvature, inhibiting fusion. The rigid amphipathic fusion inhibitors (RAFIs) are synthetic compounds of inverted cone molecular geometry. They inhibit infectivity of otherwise unrelated enveloped viruses. The leading RAFI, aUY11, has an ethynyl-perylene hydrophobic and an uracil-arabinose polar moiety. aUY11 intercalates in viral envelopes and inhibits virion-to-cell fusion of a broad spectrum of otherwise unrelated enveloped viruses. Previous studies showed that amphipathicity, rigidity, and inverted cone molecular geometry were required. We propose that the inverted cone molecular geometry of the RAFIs increases the energy barrier for the hemifusion stalk, inhibiting fusion. Then, chemically distinct compounds with similar amphipathicity, rigidity, and inverted cone shape would have similar antiviral potencies, regardless of specific chemical groups. Alternatively, the perylene group exposed to visible light may induce viral lipid peroxidation. Then, the perylene group and absorbance at visible spectrum would be required. We now evaluated twenty-five chemically distinct RAFIs. The perylene moiety and absorption at visible spectrum were not required, but a minimum length of the hydrophobic moiety was, 10.3 Å. The arabino moiety could be modified or replaced by other groups. Cytidine was not tolerated. Bilayer intercalation was required but not sufficient. The vast majority of RAFIs had no overt cytotoxicity (CC50 > 20 μM; TI > 250–1200). Carbonyl or butylamide substitutions for arabino, or cytidine replacement for uracil, increased cytotoxicity. Cytotoxicity was mainly determined by the polar moiety and there was no correlation between antiviral and cytostatic activities.The definition of the effects of shape and chemical groups of the RAFIs opens the possibility to the rational design of lipid-acting antivirals active against a broad spectrum of enveloped viruses.

Photodynamic therapy for choroidal neovascularization: a review.

To review the biophysical basis and current state of therapy for photodynamic closure of subfoveal choroidal neovascularization in the eye. A review of the literature is included, which encompasses the chemical structure, biophysical mechanism of action, range of available agents, status of clinical trials, clinical indications, results of treatments, complications, and future directions. Photodynamic therapy has been shown to be effective in closing both experimental choroidal neovascularization in animal models as well as subfoveal choroidal neovascularization in humans. The therapy results in temporary closure of choroidal new vessels for a period of approximately 1 to 4 weeks. By 12 weeks, most patients have reperfusion or reproliferation of choroidal new vessels resulting in the need for retreatment to achieve continued closure and visual stabilization. Differences exist in the quantum yield, clinical efficiency, and light and sensitizer dose requirements between different classes of agents. Further clinical trials will be required to determine the optimal form of therapy, with verteporfin (Visudyne) as the only currently approved agent. Other agents, including tin etiopurpurin (Purlytin) and motexafin lutetium (Optrin), are currently undergoing phase III, and phase II trials, respectively. Photodynamic therapy is a promising treatment modality shown to be effective in achieving closure and stabilization of vision loss compared with placebo control in eyes with subfoveal choroidal neovascularization.

The possibility of hazard in medical and industrial applications of ultrasound.

Over the past ten years ultrasound has become well established as the basis of a varied and expanding group of medical diagnostic techniques. It is also used therapeutically in a wide variety of conditions and has found further extensive application in industrial processing. The basis for its therapeutic use is that ultrasound is known to be capable, under certain conditions, of modifying or even destroying living tissue: it therefore seems important to have a clear understanding of the factors that determine whether any potentially harmful forms of biological change may arise in the course of any of the applications to which ultrasound is being put at present, or for which it may be contemplated in the future. This article reviews not only the somewhat fragmentary evidence at present available that has specific bearing on the possible hazards of current ultrasonic applications, but also the equally relevant but more fundamental question of the nature of the biophysical mechanisms of action of ultrasound....