Effect of CYP3A5*3 genetic variant on the metabolism of direct-acting antivirals in vitro : a different effect on asunaprevir versus daclatasvir and beclabuvir

Direct-acting antivirals, asunaprevir (ASV), daclatasvir (DCV), and beclabuvir (BCV) are known to be mainly metabolized by CYP3A enzymes; however, the differences in the detailed metabolic activities of CYP3A4 and CYP3A5 on these drugs are not well clarified. The aim of the present study was to elucidate the relative contributions of CYP3A4 and CYP3A5 to the metabolism of ASV, DCV, and BCV, as well as the effect of CYP3A5*3 genetic variant in vitro. The amount of each drug and their major metabolites were determined using LC-MS/MS. Recombinant CYP3As and CYP3A5*3-genotyped human liver microsomes (CYP3A5 expressers or non-expressers) were used for the determination of their metabolic activities. The contribution of CYP3A5 to ASV metabolism was considerable compared to that of CYP3A4. Consistently, ASV metabolic activity in CYP3A5 expressers was higher than those in CYP3A5 non-expresser. Moreover, CYP3A5 expression level was significantly correlated with ASV metabolism. In contrast, these observations were not found in DCV and BCV metabolism. To our knowledge, this is the first study to directly demonstrate the effect of CYP3A5*3 genetic variants on the metabolism of ASV. The findings of the present study may provide basic information on ASV, DCV, and BCV metabolisms

Asymmetrical bonding in liquid Bi disentangled by inelastic X-ray scattering

The structure of liquid Bi has been debated in relationship with the Peierls distortion, as crystalline Bi takes A7 structure. A recent ab initio molec- ular dynamics simulation for liquid Bi predicted a flat-topped profile of the acoustic dispersion curve. To confirm the prediction, we have carried out inelas- tic x-ray scattering (IXS) for liquid Bi. The dynamic structure factor obtained by the IXS exhibits a distinct inelastic excitation of the longitudinal acoustic mode up to 14 nm−1 and the dispersion curve of the excitation energy obtained by the memory function analysis becomes a flat-topped one. We found that a linear chain model including the interatomic interaction with the second near- est neighbors can explain the flat-topped profile. The result suggests that the anomalous dispersion curve in liquid Bi arises from local anisotropy related to the Peierls distortion in the crystalline phase.

エキタイ カルコゲン ノ ドウテキ コウゾウ

京都大学0048新制・課程博士博士(理学)甲第10488号理博第2714号新制||理||1387(附属図書館)UT51-2003-U458京都大学大学院理学研究科物理学・宇宙物理学専攻(主査)教授 八尾 誠, 教授 水崎 隆雄, 教授 小貫 明学位規則第4条第1項該当Doctor of ScienceKyoto UniversityDA

61. Time-resolved small-angle x-ray scattering studies on the formation of Bacterial Cellulose(poster presentation,Soft Matter as Structured Materials)

この論文は国立情報学研究所の電子図書館事業により電子化されました。バクテリアセルロース(BC)の形成過程を時分割小角・超小角X線散乱測定し、X線による菌体の大きさの見積もりと、菌の増殖過程の測定に初めて成功した。また、BCは0.01nm^程度の波数領域においては2.5次元のフラクタル構造を有することが分かった

Data_Sheet_1_Efficient elimination of RNA mycoviruses in aspergillus species using RdRp-inhibitors ribavirin and 2’-C-methylribonucleoside derivatives.xlsx

RNA viruses in fungi (mycoviruses) are model systems for understanding the relationships between eukaryotic microorganisms and RNA viruses. To reveal the effects of mycoviruses on host fungi, it is essential to compare the phenotypes between isogenic fungal isolates with or without RNA virus infection. Since active entry machinery for RNA mycoviruses has never been identified, introducing mycoviruses to fungi is a difficult and time-consuming process. Therefore, most studies have tried to generate virus-free isolates from infected strains by eliminating the mycovirus. However, methods of elimination have not been evaluated in a quantitative and comparative manner. In this study, we established a method to remove mycoviruses from host cells using the antiviral drugs ribavirin, 2′-C-methylcytidine (2CMC), 2′-C-methyladenosine (2CMA), and 7d2CMA, and compared the efficiency of removal in virus-infected strains of Aspergillus fumigatus. The results indicated that treatment with the drugs removed RNA viruses of diverse proportions in the families Chrysoviridae, Mitoviridae, Partitiviridae, Polymycoviridae, and an unclassified RNA virus group. Viruses belonging to Narnaviridae were hardly eliminated by these antiviral treatments when they were the sole infectious agents. We found that 2CMC showed activity against a wider range of RNA mycoviruses compared to ribavirin, 2CMA, and 7d2CMA, although 7d2CMA also efficiently removed dsRNA viruses from the families Chrysoviridae, Partitiviridae, and Polymycoviridae. These results indicated that removal of mycoviruses depends on the specific viral species and antiviral drug. This is the first report demonstrating a preferential antiviral effect against mycoviruses, which will enhance research on microbial RNA viruses and support their elimination from economically important fungi such as edible mushrooms.</p