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ACS Infect. Dis.这个期刊封面,看着就热! 精选

已有 1090 次阅读 2020-5-27 08:47 |系统分类:科研笔记

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Title:Molecular Hybridization-Inspired Optimization of Diarylbenzopyrimidines as HIV-1 Nonnucleoside Reverse Transcriptase Inhibitors with Improved Activity against K103N and E138K Mutants and Pharmacokinetic Profiles



封面设计师:Bill  学术支持:Echo

项目编号:SD20190819f-15


2020年5月份,复旦大学陈芬儿院士,庄春林博士在期刊ACS Infect. Dis.上发表文章。


此次松迪设计的图像被选为期刊封面,让我们走进今天的封面故事。

  

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文章链接:
https://pubs.acs.org/doi/10.1021/acsinfecdis.9b00229

摘要:
Molecular hybridization is a powerful strategy in drug discovery. A series of novel diarylbenzopyrimidine (DABP) analogues were developed by the hybridization of FDA-approved drugs etravirine (ETR) and efavirenz (EFV) as potential HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs). Substituent modifications resulted in the identification of new DABPs with the combination of the strengths of the two drugs, especially compound 12d, which showed promising activity toward the EFV-resistant K103N mutant. 12d also had a favorable pharmacokinetic (PK) profile with liver microsome clearances of 14.4 μL/min/mg (human) and 33.2 μL/min/mg (rat) and an oral bioavailability of 15.5% in rat. However, its activity against the E138K mutant was still unsatisfactory; E138K is the most prevalent NNRTI resistance-associated mutant in ETR treatment. Further optimizations resulted in a highly potent compound (12z) with no substituents on the phenyl ring and a 2-methyl-6-nitro substitution pattern on the 4-cyanovinyl-2,6-disubstitued phenyl motif. The antiviral activity of this compound was much higher than those of ETR and EFV against the WT, E138K, and K103N variants (EC50 = 3.4, 4.3, and 3.6 nM, respectively), and the cytotoxicity was decreased while the selectivity index (SI) was increased. In particular, this compound exhibited acceptable intrinsic liver microsome stability (human, 34.5 μL/min/mg; rat, 33.2 μL/min/mg) and maintained the good PK profile of its parent compound EFV and showed an oral bioavailability of 16.5% in rat. Molecular docking and structure–activity relationship (SAR) analysis provided further insights into the binding of the DABPs with HIV-1 reverse transcriptase and provided a deeper understanding of the key structural features responsible for their interactions.


如今国际期刊上频现国风,中国学者也越来越爱将中国传奇故事与现代科研相结合。


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嫦娥奔月、女娲补天、梁祝


在本次封面中也采用了以古代神话为核心的设计思路,借鉴了后羿射日的故事。

众所周知,后羿是中国远古五帝时期的神话人物,帝尧的射师,嫦娥的丈夫,神话传说中的射日英雄。在设计中我们首先绘制出了这位故事主人公的形象。

他头戴金盔身批金甲,弓步立于悬崖之上,只待利箭应弦而发。


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让我们放大看看后羿的利箭,箭身周围包裹着一层白色柔光,仿佛神话电视剧中的“特效”一般。

而这个“特效”就代表着论文研究的主体——新型的二芳基苯并嘧啶(DABP)类似物的一种


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与此同时,可以看到天上有许多个“太阳”;太阳的形态与橘色的球形病毒非常相似,用来代指再适合不过了。

以下是两颗还未被箭射中的太阳。

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而更多的“太阳”已经被带有DABP的利箭射中。


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整体封面所展示的内容在借助神话进行表达之后变得非常清晰易懂,同时又因此引入了故事性而更加生动有趣。

让人在领悟现代科研学者智慧结晶的同时,也不由感叹古代人民天马行空的想象力。


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