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A new class of small molecules that bind the HCV RNA IRES IIA subdomain with sub-micromolar affinity is reported. The benzimidazole ‘hit' 1 with a KD ~100 μM to a 29-mer RNA model of Domain IIA was identified from a 180000-member library using mass spectrometry-based screening methods. Further MS-assisted SAR (structure−activity relationships) studies afforded benzimidazole derivatives with sub-micromolar binding affinity for the IIA RNA construct. The optimized benzimidazoles demonstrated activity in a cellular replicon assay at concentrations comparable to their KD for the RNA target.

Sex ratio theory posits that the adaptive proportion of male to female gametocytes of a malaria parasite within the vertebrate host depends on the degree of inbreeding within the vector. Gametocyte sex ratio could be phenotypically flexible, being altered based on the infection's clonal diversity, and thus likely inbreeding. This idea was tested by manipulating the clonal diversity of infections of Plasmodium mexicanum in its lizard host, Sceloporus occidentalis. Naive lizards were inoculated with infected blood from a single donor or 3 pooled donors. Donors varied in their gametocyte sex ratios (17–46% male), and sex ratio theory allowed estimation of the clonal diversity within donor and recipient infections. Phenotypic plasticity would produce a correlation between donor and recipient infections for infections initiated from a single donor, and a less female-biased gametocyte sex ratio in recipients that received a mixed blood inoculum (with predicted higher clonal diversity) than recipients receiving blood from a single donor. Neither pattern was observed. Gametocyte sex ratio of most infections ranged from 35 to 42% male, expected if clonal diversity was high for all infections. Alternative explanations are suggested for the observed variation of gametocyte sex ratio among P. mexicanum infections.

A technique for lead discovery vs RNA targets utilizing mass spectrometry (MS) screening methods is described. The structure−activity relationships (SAR) derived from assaying weak binding motifs allows the pharmacophores discovered to be elaborated via “SAR by MS” to higher affinity ligands. Application of this strategy to a subdomain of the 23S rRNA afforded a new class of compounds with functional activity.

A mixture-based combinatorial library of 14-membered macrocycles was synthesized to target ribosomal RNA and uncover a new class of antibacterial agents. High-throughput screening identified a macrocyclic mixture that inhibited cell-free-coupled transcription/translation in Escherichia coli-derived extracts, with an IC50 value in the 25−50 μM range. In a follow-up library of 64 single macrocycles, 8 gave IC50 values ranging from 12 to 50 μM in the cell-free protein synthesis inhibition assay. Some of the macrocycles were screened in a translation inhibition assay, and IC50 values generally paralleled those obtained in the uncoupled transcription/translation assay. Additional analogues were prepared in a preliminary structure−activity relationship study, and more potent macrocycles were identified with low micromolar activity (IC50 values = 2−3 μM). Some of these macrocycles displayed antibacterial activity against lipopolysaccharide mutant E. coli bacterial cells (IC50 values = 12−50 μM).

More than a year ago Coggeshall1 pointed out the possibilities of the spread of malaria in wartime to civilians. As far as I can determine, the periodical literature for the past two years has contained very few references to the occurrence of malaria cases in new areas or an increase in prevalence of malaria in endemic areas since the war. Jeffries2 reported 1 case of estivoautumnal malaria occurring in a merchant seaman who returned to Oregon. However, there had been no report of any secondary cases arising. My purpose in the present discussion is to report 2 cases of tertian malaria and the evidence from which I conclude that a returned soldier was the source: CASE 1 —R. C., a white girl aged 12 years, a student, was seen in the office on Aug. 5, 1944 complaining of chills and fever of one week's duration. Since the child