Genetic diversity of coxsackie A viruses (CAVs) and enteroviruses 68, 69, and 71 was studied by comparing nucleotide and derived amino acid sequences from the 5' untranslated region (5'UTR), VP4-VP2 capsid protein and polymerase 3D region, and 3'UTR. The data were obtained by sequencing PCR amplicons. According to the molecular analysis of the coding region, CAVs belong to three different genetic clusters. CAV2, 3, 5, 7, 8, 10, 12, 14, and 16 form a coherent genetic group designated cluster A. No other enteroviruses, apart from enterovirus 71, are found in this cluster. CAV9 is the only member of the subgroup found in the same genetic group with coxsackie B viruses, the major group of echoviruses and enterovirus 69 (cluster B). Cluster C includes CAV1, 11, 13, 15, 17, 18, 19, 20, 21, 22, and 24 which are genetically close relatives of polioviruses. Enterovirus 68 is related to enterovirus 70 (cluster D). Clusters different from those in the coding region are found in the 5'UTR while the grouping in the 3'UTR is similar to that found in the capsid region. Correlation of these findings with evolution, pathogenesis, and classification is discussed.

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 2 AbstractLowering local estradiol concentration by inhibition of the estradiol-synthesizing enzyme 17β-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) has been proposed as a promising new therapeutic option to treat estrogen dependent diseases like endometriosis and breast cancer. Based on a molecular modelling approach we designed and synthesized novel C15-substituted estrone derivatives. Subsequent biological evaluation revealed that potent inhibitors of human 17beta-HSD1 can be identified in this compound class. The best, compound 21, inhibited recombinant human 17beta-HSD1 with an IC50 of 10 nM and had no effect on the activity of recombinant human 17β-hydroxysteroid dehydrogenase type 2 (17beta-HSD2), the enzyme catalyzing estradiol inactivation. These properties were retained in a cell-based enzyme activity assays. In spite of the estrogen backbone compound 21 did not show estrogen receptor mediated effects in vitro or in vivo.In conclusion, estrone C15 derivative compound 21 can be regarded as a promising lead compound for further development as a 17beta-HSD1 inhibitor.

Local estrogen production plays a key role in proliferative endometrial disorders, such as endometrial hyperplasia and cancer. Hydroxysteroid (17␤) dehydrogenase 1 (HSD17B1) is an enzyme that catalyzes with high efficiency the conversion of weakly active estrone into highly potent estradiol. Here we report that female transgenic mice expressing human HSD17B1 invariably develop endometrial hyperplasia in adulthood. These mice also fail to ovulate and have enhanced peripheral conversion of estrone into estradiol in a variety of target tissues, including the uterus. As in humans, endometrial hyperplasia in HSD17B1 transgenic female mice was reversible on ovulation induction , which triggers a rise in circulating progesterone levels , and in response to exogenous progestins. Strikingly , a treatment with an HSD17B1 inhibitor failed to restore ovulation yet completely reversed the hyperplastic morphology of epithelial cells in the glandular compartment , although less so in the luminal epithelium. The data indicate that human HSD17B1 expression enhances endometrial estrogen production, and consequently, estrogen-dependent proliferation. Therefore, HSD17B1 is a promising new therapeutic target in the management of estrogen-dependent endometrial diseases.