In vivo efficacy of SDZ 35-682, a new picornavirus capsid-binding agent.

SDZ 35-682 is a potent and selective inhibitor of the replication of members of the picornavirus group. It belongs to the group of uncoating inhibitors binding to the hydrophobic pocket in the capsid of the virion. In cell culture it inhibits several rhinovirus serotypes and echovirus 9 at concentrations as low as 0.1 micrograms/ml. In the echovirus 9 animal model the protective effect of SDZ 35-682 was found to be dependent on both, dose of drug and duration of treatment. Significant protection of newborn mice from paralysis and death could be achieved by either a high dose (126 mg/kg) given only twice, at days 0 and 1 relative to echovirus 9 inoculation, or by a lower dose administered for 4 or 6 days. This finding might be explained by assuming a long half-life for SDZ 35-682. Though clinical usefulness of SDZ 35-682 may be limited by its relatively narrow antiviral spectrum it represents a novel potent and selective inhibitor of rhinovirus and echovirus 9 replication in cell culture and in the organism.

SDZ 35-682, a new picornavirus capsid-binding agent with potent antiviral activity.

SDZ 35-682 is a potent and selective inhibitor of the replication of members of the picornavirus group. It inhibits several rhinovirus serotypes and echovirus 9 at concentrations as low as 0.1 micrograms/ml, without exerting any effect on cell proliferation up to 30 micrograms/ml. As observed with other capsid-binding antipicornavirus compounds, there is a wide variation in sensitivity of the different serotypes within the rhinovirus group. The point of interference of SDZ 35-682 in a single cycle of virus growth is an early event taking place before 2 or 3 h of echo- or rhinovirus replication, respectively. By incorporation of neutral red into the viral capsid and measurement of acquisition of photoresistance it is shown that uncoating of echovirus 9 is inhibited by SDZ 35-682. In addition, efficiency of adsorption of echovirus 9 is reduced by SDZ 35-682. To demonstrate that SDZ 35-682, like other uncoating inhibitors of picornaviruses, binds to the hydrophobic pocket beneath the canyon floor co-crystallization with HRV 14 was performed. Considerable conformational changes occur in VP1 in the HRV 14/SDZ 35-682 complex. SDZ 35-682 is 19 A long from end to end and thus fills the entire hydrophobic pocket including its innermost end; it is less flexible than other long antiviral agents. It has been suggested that compounds filling the entire hydrophobic pocket will affect the uncoating process of the virion. Thus, inhibition of viral uncoating, as demonstrated with echovirus 9, probably is the predominant mode of action of SDZ 35-682.

The effects of fractions (chalones) obtained from lymphoid organs on lymphocyte proliferation in vitro.

Aqueous extracts of lymphoid organs were prepared and fractionated by means of gel filtration, ion exchange chromatography, and isoelectric focusing. A protein-containing fraction with a molecular weight of approximately 80,000--90,000 and isoelectric points of 7.6 and 5.3--6.2 was isolated and shown to inhibit reproducibly both thymidine incorporation and proliferation of concanavalin A-stimulated mouse spleen lymphocytes in vitro. This effect appeared specific since proliferation of mastocytoma P-815 and leukemia L-1210 cells remained unaffected. A small molecular weight fraction (500 to 10,000 daltons) was also found to inhibit lymphocyte proliferation in vitro but was without apparent specificity for cell type.

Septamycin, a polyether antibiotic. Taxonomy, fermentation, isolation and characterization.

Septamycin is a metal complexing polyether antibiotic produced by a strain of Streptomyces hygroscopicus NRRL 5678. The metabolite, a monocarboxylic acid, was isolated as the sodium salt C48H81NaO16. The crystal structure and absolute configuration were established by X-ray analysis of the p-bromophenacyl derivative. Septamycin has a thirty-carbon backbone and contains seven heterocyclic rings. Supported by direct comparison septamycin proved to be identical with antibiotic A28695 A isolated from Streptomyces albus NRRL 3883. The metabolite is active against gram-positive bacteria and Eimeria tenella (chicken coccidiosis).