In vivo antiviral efficacy of prenylation inhibitors against hepatitis delta virus

Hepatitis delta virus (HDV) can dramatically worsen liver disease in patients coinfected with hepatitis B virus (HBV). No effective medical therapy exists for HDV. The HDV envelope requires HBV surface antigen proteins provided by HBV. Once inside a cell, however, HDV can replicate its genome in the absence of any HBV gene products. In vitro, HDV virion assembly is critically dependent on prenyl lipid modification, or prenylation, of its nucleocapsid-like protein large delta antigen. To overcome limitations of current animal models and to test the hypothesis that pharmacologic prenylation inhibition can prevent the production of HDV virions in vivo, we established a convenient mouse-based model of HDV infection capable of yielding viremia. Such mice were then treated with the prenylation inhibitors FTI-277 and FTI-2153. Both agents were highly effective at clearing HDV viremia. As expected, HDV inhibition exhibited duration-of-treatment dependence. These results provide the first preclinical data supporting the in vivo efficacy of prenylation inhibition as a novel antiviral therapy with potential application to HDV and a wide variety of other viruses

Module assembly for designing multivalent mid-sized inhibitors of protein-protein interactions.

Developing clinically relevant synthetic agents that are capable of disrupting protein-protein interactions (PPIs) is now a major goal of scientific research. In an effort to explore new methodologies that are applicable to the design of synthetic PPI inhibitors, we examined a strategy based on the assembly of small module compounds to create multivalent mid-sized agents. This personal account describes three particular approaches based on module assembly: metal-chelating-based ligand assembly, covalent chemical ligation templated by a targeted protein, and bivalent inhibitor design for simultaneous targeting of the active pocket and protein surface. These strategies were shown to be useful for synthesizing minimally sized synthetic agents for targeting PPIs and may enable development of agents that are applicable to inhibition of intracellular PPIs

STUDIES ON SYNTHESIS, REACTION, AND IRON-CHELATING PROPERTY OF N-HYDROXYAMIDE-CONTAINING HETEROCYCLES

報告番号: 乙13019 ; 学位授与年月日: 1996-09-19 ; 学位の種別: 論文博士 ; 学位の種類: 博士(工学) ; 学位記番号: 第13019号 ; 研究科・専攻: 工学系研究科化学生命工学専

たんぱく質間相互作用を制御する天然物誘導体の合成と機能

平成27年度 京都大学化学研究所 スーパーコンピュータシステム 利用報告

Intrinsically Disordered Proteins as Regulators of Transient Biological Processes and as Untapped Drug Targets

Intrinsically disordered proteins (IDPs) are critical players in the dynamic control of diverse cellular processes, and provide potential new drug targets because their dysregulation is closely related to many diseases. This review focuses on several medicinal studies that have identified low-molecular-weight inhibitors of IDPs. In addition, clinically relevant liquid–liquid phase separations—which critically involve both intermolecular interactions between IDPs and their posttranslational modification—are analyzed to understand the potential of IDPs as new drug targets

N-ヒドロキシアミド含有複素環の合成、反応および鉄キレート特性に関する研究

University of Tokyo (東京大学

In Vitro And In Vivo Antimalarial Activity Of Peptidomimetic Protein Farnesyltransferase Inhibitors With Improved Membrane Permeability

A series of ester derivatives of 17 with increased lipophilicity were synthesized and tested against P. falciparum in red blood cells, where the benzyl ester derivative 16 exhibited the best inhibition activity (ED 50 = 150 nM). Compound 16 showed in vivo antimalarial activity by 46.1% at a daily dose of 50 mg kg -1 using murine malaria models infected with Plasmodium berghei. A series of protein farnesyltransferase inhibitor ester prodrugs of FTI-2148 (17) were synthesized in order to evaluate the effects of ester structure modification on antimalarial activity and for further development of a farnesyltransferase inhibitor with in vivo activity. Evaluation against P. falciparum in red blood cells showed that all the investigated esters exhibited significant antimalarial activity, with the benzyl ester 16 showing the best inhibition (ED 50 = 150 nM). Additionally, compound 16 displayed in vivo activity and was found to suppress parasitemia by 46.1% at a dose of 50 mg kg -1 day -1 against Plasmodium berghei in mice. The enhanced inhibition potency of the esters is consistent with improved cell membrane permeability compared to that of the free acid. The results of this study suggest that protein farnesyltransferase is a valid antimalarial drug target and that the antimalarial activity of these compounds derives from a balance between the hydrophobic character and the size and conformation of the ester moiety. © 2004 Elsevier Ltd. All rights reserved