[Dithiols as chelators. A cause of bullous skin reactions]. / Chelatbildner mit Thiolaktivität. Auslöser bullöser Hautreaktionen.

Chelation therapy with (RS)-2,3-Bis(sulfonyl)propane-1-sulfonic acid (DMPS) after an occupational lead exposure led to the development of a severe bullous drug eruption. Skin tests and histology/immunohistology of the test reactions indicated a T-cell-mediated immune response against DMPS. Metal-binding thiol groups as in DMPS are chemically highly reactive and therefore effectively mediate the development of immunogenic hapten (DMPS)-protein complexes. Therefore, the pharmacological effects and sensitization potential of dithiols are tightly connected. Cross-reactivity of DMPS to other chelators like D-penicillamine is possible; the indications for chelation therapy should be weighed carefully.

Dissociation of the signalling and antiviral properties of SDF-1-derived small peptides.

BACKGROUND: The chemokine receptor CXCR4 (a receptor for the Cys-X-Cys class of chemokines) is a CD4-associated coreceptor for T-cell-tropic strains of human immunodeficiency virus 1 (HIV-1) and represents a target for antiviral therapy. Infection by T-tropic HIV-1 can be blocked by stromal-cell-derived factor-1 (SDF-1), the natural ligand of CXCR4. The broad variety of cells expressing CXCR4 and the perturbations observed in mice deficient for SDF-1 suggest that antiviral compounds antagonizing the signalling activity of CXCR4 might have severe side effects in vivo. Compounds that interfere selectively with HIV entry and not with SDF-1 signalling would therefore be useful. RESULTS: A series of peptides, each of 13 residues, spanning the whole SDF-1alpha sequence were tested for their ability to block HIV-1 infection. The antiviral and signalling properties of SDF-1 were retained by a peptide corresponding to its amino terminus. Removal of the first two residues resulted in an antiviral antagonist of the SDF-1-CXCR4 signalling pathway. We prepared 234 single-substitution analogues and identified one antiviral analogue that had drastically reduced agonistic or antagonistic properties. The antiviral peptides competed with the monoclonal antibody 12G5 for CXCR4 binding. Their antiviral activity seems to be due to receptor occupancy rather than induction of receptor endocytosis. CONCLUSIONS: The amino terminus of the SDF-1 chemokine is sufficient for signal transduction via CXCR4 and for inhibition of HIV-1 entry, but these activities could be dissociated in a peptide analogue. This peptide represents a lead molecule for the design of low molecular weight antiviral drugs.

A patch-clamp study of the partial agonist actions of tubocurarine on rat myotubes.

Single channels activated by (+)-tubocurarine (curare) were recorded from rat myotubes using the patch-clamp technique. The agonist-like action of curare does not result from a contaminant molecule, as the same effects were observed with curare purified by high-performance liquid chromatography. A curare-activated channel can adopt two levels of conductance: full (F) or partial (P). The F state has a slope conductance of 40 pS (identical to that of the acetylcholine (ACh)-activated channel) and the P state has a conductance of 13 pS. At low concentrations of agonist (ACh or curare), the distribution of channel open times is biphasic. The briefer channels may result from the binding of a single agonist molecule whereas the longer-lived channels probably occur following the binding of two agonist molecules. The mean open time of the F state decreases with increasing curare concentration. It is shown that band-width limitations are likely to account for only a very small part of this observed reduction. In contrast, the mean open time of the P state is independent of the concentration of curare. A simple interpretation is that the F state is susceptible to channel blockade by curare, whereas the P state is not. The P state preceded the F state almost as often as it followed the F state; it can also be observed separately from the F state. The fraction of events including a P state increases from about 4% in the presence of 1 microM-curare to 30% at 100 microM-curare. This fraction is also increased by hyperpolarization. When the curare concentration is increased, the F-state frequency first increases and then decreases at higher concentration. This frequency is also decreased by hyperpolarization. The decrease in F-state frequency is probably related to channel blockade by curare; it cannot be wholly accounted for by problems associated with limited time resolution. A synthetic analogue of curare, (+)- tubocurine dimethiodide presents an agonist activity similar to that of curare but with a faster closing rate for both F and P states. The various actions of curare are summarized in two possible models where the P state is interpreted as either a partially open channel or a channel which is partially blocked.

Curare can open and block ionic channels associated with cholinergic receptors.

Curare has long been regarded as a typical competitive antagonist of acetylcholine (ACh) at the vertebrate neuromuscular junction. Recently, however, it has been shown that curare can also block the channels opened by ACh at the frog neuromuscular junction as well as on rat and Aplysia neurones; moreover, curare is able to depolarize rat myotubes and thus behaves as an agonist for the cholinergic receptor of this preparation (see ref. 6). Using the single channel recording technique, we have now found that, on rat myotubes, curare can both open and block in the same cell the channels controlled by the cholinergic receptor.