A platform of assays for the discovery of anti-Zika small-molecules with activity in a 3D-bioprinted outer-blood-retina model.
A platform of assays for the discovery of anti-Zika small-molecules with activity in a 3D-bioprinted outer-blood-retina model.
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DOI：
10.1371/journal.pone.0261821
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发表时间：
2022
期刊：
影响因子：
3.7
通讯作者：
Simeonov A
中科院分区：
文献类型：
--
作者：
Dorjsuren D;Eastman RT;Song MJ;Yasgar A;Chen Y;Bharti K;Zakharov AV;Jadhav A;Ferrer M;Shi PY;Simeonov A
寨卡病毒（ZIKV）是一种节肢动物传播的黄病毒，可引起严重的新生儿神经系统疾病，其爆发引发的全球卫生紧急情况已经消退，但在流行地区仍有ZIKV的传播。因此，仍然存在发现和开发针对ZIKV的治疗性干预的医学需求。为了鉴定抑制ZIKV疾病和传播的小分子化合物，我们筛选了多个小分子集合，主要来源于天然产物，用于它们抑制野生型ZIKV的能力。作为主要的高通量筛选，我们使用了在Vero细胞中进行的病毒致细胞病变效应（CPE）抑制试验，该试验经过优化并小型化至1536孔格式。使用重组寨卡病毒在一组正交测定中测试从初步筛选鉴定的合适的活性化合物，包括ZIKV海肾荧光素酶报告基因测定和ZIKV mCherry报告基因系统。进一步评估在野生型ZIKV抑制和ZIKV报告基因测定中有活性的化合物对其他黄病毒的抑制作用。最后，我们证明了野生型ZIKV能够感染3D生物打印的外血视网膜屏障组织模型，并破坏其屏障功能，如通过电阻测量的。鉴定的化合物之一（3-乙酰基-13-脱氧phomenone，NCGC 00380955）能够预防病毒感染对该临床相关ZIKV感染模型的病理作用。
The global health emergency posed by the outbreak of Zika virus (ZIKV), an arthropod-borne flavivirus causing severe neonatal neurological conditions, has subsided, but there continues to be transmission of ZIKV in endemic regions. As such, there is still a medical need for discovering and developing therapeutical interventions against ZIKV. To identify small-molecule compounds that inhibit ZIKV disease and transmission, we screened multiple small-molecule collections, mostly derived from natural products, for their ability to inhibit wild-type ZIKV. As a primary high-throughput screen, we used a viral cytopathic effect (CPE) inhibition assay conducted in Vero cells that was optimized and miniaturized to a 1536-well format. Suitably active compounds identified from the primary screen were tested in a panel of orthogonal assays using recombinant Zika viruses, including a ZIKV Renilla luciferase reporter assay and a ZIKV mCherry reporter system. Compounds that were active in the wild-type ZIKV inhibition and ZIKV reporter assays were further evaluated for their inhibitory effects against other flaviviruses. Lastly, we demonstrated that wild-type ZIKV is able to infect a 3D-bioprinted outer-blood-retina barrier tissue model and disrupt its barrier function, as measured by electrical resistance. One of the identified compounds (3-Acetyl-13-deoxyphomenone, NCGC00380955) was able to prevent the pathological effects of the viral infection on this clinically relevant ZIKV infection model.
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影响因子：
3.8
作者：
CABRAL, GA;MCNERNEY, PJ;MISHKIN, EM
通讯作者：
MISHKIN, EM
影响因子：
39.2
作者：
Costa F;Sarno M;Khouri R;de Paula Freitas B;Siqueira I;Ribeiro GS;Ribeiro HC;Campos GS;Alcântara LC;Reis MG;Weaver SC;Vasilakis N;Ko AI;Almeida AR
通讯作者：
Almeida AR
影响因子：
30.3
作者：
Barrows NJ;Campos RK;Powell ST;Prasanth KR;Schott-Lerner G;Soto-Acosta R;Galarza-Muñoz G;McGrath EL;Urrabaz-Garza R;Gao J;Wu P;Menon R;Saade G;Fernandez-Salas I;Rossi SL;Vasilakis N;Routh A;Bradrick SS;Garcia-Blanco MA
通讯作者：
Garcia-Blanco MA
DOI：
10.1111/cts.12570
发表时间：
2018-09
期刊：
Clinical and translational science
影响因子：
--
作者：
Coussens NP;Sittampalam GS;Guha R;Brimacombe K;Grossman A;Chung TDY;Weidner JR;Riss T;Trask OJ;Auld D;Dahlin JL;Devanaryan V;Foley TL;McGee J;Kahl SD;Kales SC;Arkin M;Baell J;Bejcek B;Gal-Edd N;Glicksman M;Haas JV;Iversen PW;Hoeppner M;Lathrop S;Sayers E;Liu H;Trawick B;McVey J;Lemmon VP;Li Z;McManus O;Minor L;Napper A;Wildey MJ;Pacifici R;Chin WW;Xia M;Xu X;Lal-Nag M;Hall MD;Michael S;Inglese J;Simeonov A;Austin CP
通讯作者：
Austin CP
影响因子：
--
作者：
Eyer L;Nencka R;de Clercq E;Seley-Radtke K;Růžek D
通讯作者：
Růžek D