Ebolavirus causes sporadic outbreaks of lethal hemorrhagic fever in humans with no currently approved therapy. Cells take up Ebolavirus by macropinocytosis, followed by trafficking through endosomal vesicles. However, few factors controlling endosomal virus movement are known. Here we find that Ebolavirus entry into host cells requires the endosomal calcium channels called two pore channels (TPCs). Disrupting TPC function by gene knockout, small interfering RNAs or small molecule inhibitors halted virus trafficking and prevented infection. Tetrandrine, the most potent small molecule we tested, inhibited infection of human macrophages, the primary target of Ebolavirus in vivo, and also showed therapeutic efficacy in mice. Therefore, TPC proteins play a key role in Ebolavirus infection and may be effective targets for antiviral therapy.

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We report the formal synthesis of angiogenesis inhibitor NM-3 (1) in six steps from either of the 2,4-dimethoxyhalobenzenes 13a,b or 3,5-dimethoxychlorobenzene (13c). The first key reaction is the regiospecific alkylation/rearrangement between the aryne derived from 13a-c with sodium diethylmalonate in THF to produce diester 11, which after hydrolysis and cyclization affords homophthalic anhydride 3. The second is the reaction of anhydride 3 with either ethyl 2-methylmalonate (28a), in the presence of 1,1'-carbonyldiimidazole, or ethyl-2-methylmalonyl chloride (28b) under basic conditions to afford key isocoumarin 27. The conversion of 27 constitutes a formal synthesis of NM-3.

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M«0'^S^V'NH 'o chemists can play a leading role here. From their experiences in probing reaction mechanisms in vitro they can postulate likely intermediate metabolites and design experiments to follow the reaction sequences of drugs".2The majority of antitumor antibiotics inhibit cell division by interfering with the synthesis or use of nucleic acids.3 There is a constant need to discover new agents that interact with DNA in a mechanistically definable manner.4 In 1987 the Lederle5 and Bristol-Myers6 groups reported the unprecedented structures of calicheamicin 7i (1), esperamicin A, (2), Alb (3), and A2 (4), and the metabolite esperamicin X (5) (Chart I). They were isolated from fermentations of Micromonospora echinospora sp. calichensis and cultures of Actinomadura verrucosospora BBM 1675 and ATCC 39334, respectively. At present, these compounds are the most potent antitumor antibiotics known, being approximately 103 more active than adriamycin against murine tumors, and represent a new class of natural products based upon the Z-enediyne functionality.While they contain a number of unusual structural features such as the allylic trisulfide, a hydroxylamino sugar, and a Q-Q bridgehead double bond, it is the Z-enediyne that embues these molecules with a unique mechanism for cleaving DNA. It was proposed5'6 that the trisulfide is cleaved by nucleophilic attack at the central sulfur atom to give the thiol (or thiolate) 7, which can conjugatively add to Q to give the dihydrothiophene derivative(2) Ferguson, L. N. Chem. Soc. Rev. 1975, 4, 289.