人Polo样激酶1活性缺失突变体和结构域在293细胞中的瞬时表达

目的:构建人Polo样激酶1(Plk1)活性缺失突变体及结构域突变体的真核表达载体,并在293细胞中表达。方法:用二次PCR方法扩增Plk1基因并点突变,将82位赖氨酸突变为精氨酸,定向克隆到pcDNA3-Flag载体中;用普通PCR方法扩增Plk1激酶区域及Polo盒区域(PBD)基因,定向克隆到pcDNA3-Flag载体中;将上述质粒转染293细胞进行瞬时表达,Western印迹检测Plk1蛋白的表达。结果:构建了Flag-Plk1(K82R)、Flag-Plk1KD、Flag-Plk1PBD真核表达质粒,在293细胞中均可有效表达,蛋白相对分子质量分别为68×103、45×103、31×103。结论:在293细胞中表达了Flag-Plk1(K82R)、Flag-Plk1KD、Flag-Plk1PBD蛋白,有助于进一步探究Plk1对底物的功能。     

Upregulated Polo-Like Kinase 1 Expression Correlates with Inferior Survival Outcomes in Rectal Cancer

Background

Human polo-like kinase 1 (PLK1) expression has been associated with inferior outcomes in colorectal cancer. Our aims were to analyse PLK1 in rectal cancer, and its association with clinicopathological variables, overall survival as well as tumour regression to neoadjuvant treatment.

Methods

PLK1 expression was quantified with immunohistochemistry in the centre and periphery (invasive front) of rectal cancers, as well as in the involved regional lymph nodes from 286 patients. Scores were based on staining intensity and percentage of positive cells, multiplied to give weighted scores from 1–12, dichotomised into low (0–5) or high (6–12).

Results

PLK1 scores in the tumour periphery were significantly different to adjacent normal mucosa. Survival analysis revealed that low PLK1 score in the tumour periphery had a hazard ratio of death of 0.59 in multivariate analysis. Other predictors of survival included age, tumour depth, metastatic status, vascular and perineural invasion and adjuvant chemotherapy. There was no statistically significant correlation between PLK1 score and histological tumour regression in the neoadjuvant cohort.

Conclusion

Low PLK1 score was an independent predictor of superior overall survival, adjusting for multiple clinicopathological variables including treatment.     

Polo-Like Kinase 1 in the Life and Death of Cancer Cells

The polo-like kinase family plays a vital role in many cell cycle related events. The family includes mammalian Plk1, Snk (Plk2), and Fnk/Prk (Plk3), Xenopus laevis Plx1, Drosophila polo, fission yeast Plo1, and budding yeast Cdc5. These enzymes, in addition to a conserved kinase domain at the N-terminus, have highly conserved sequences called polo-box(s) in the non-catalytic C-terminal domain.1 Genetic and biochemical experiments with several different organisms have documented that polo-like kinases are involved in many aspects of the cell cycle, such as activation of Cdc2, centrosome assembly and maturation, activation of the anaphase-promoting complex (APC) during the metaphase-anaphase transition, and cytokinesis.(1-3)     

Hemodynamic Based Surgical Decision on Sequential Graft and Y-Type Graft in Coronary Artery Bypass Grafting

Purpose: Sequential graft and Y-type graft are two different surgical procedures in coronary artery bypass grafting (CABG). The hemodynamic environment of them are different, that may cause different short-term surgical result and long-term patency. In this study, the short-term and long-term result of sequential and Y-type graft was discussed by comparing the hemodynamics of them. Materials and Methods: Two postoperative 3-dimensional (3D) models were built by applying different graft on a patient-specific 3D model with serious stenosis. Then zero-dimensional (0D)/3D coupled simulation was carried out by coupling the postoperative 3D models with a 0D lumped parameter model of the cardiovascular system. Results: The flow rate of native coronary arteries and grafts are all calculated and illustrated in this paper. No significant difference of the native coronary arteries flow and graft flow exists between two surgical procedures. The wall shear stress (WSS) and streamline were also depicted. The graft WSS of sequential graft is 19.1% higher than Y-type graft. While flow separation appears at the bifurcation of Y-type graft. Conclusion: The short-term outcomes of sequential graft and Y-type graft are almost the same. But it can be found from the hemodynamics factors that the longterm patency of the sequential graft is better.     

人静脉移植物基质金属蛋白酶-2和波型蛋白的表达

目的:探讨人静脉移植物基质金属蛋白酶-2(Matrix Metalloproteinase-2,MMP-2)和波型蛋白(Vimentin)的表达情况。方法:应用免疫荧光组织化学技术对30个静脉移植物再塞标本中MMP-2、Vimentin的表达进行了检测,用激光共聚焦显微镜拍片,图片用Silicon Graphics Octane进行处理。结果:在正常静脉血管,有少量MMP-2的表达;Vimentin的表达较弱。在静脉移植的血管, MMP-2的表达显著增加,是正常血管的3．5倍;Vimentin(波形蛋白)在中膜和内膜的表达明显增多。另外,统计分析表明MMP-2在新内膜的表达均显著高于在中膜的表达(P＜0．01)。结论:在静脉移植物的新内膜,MMP-2和Vimentin的表达均上调,提示这些重要分子在新内膜的形成和静脉再狭窄的病理过程中具有重要的作用。     

Decreased Expression of Vitamin D Receptors in Neointimal Lesions following Coronary Artery Angioplasty in Atherosclerotic Swine

Background

Inflammatory cytokines, such as TNF-α, play a key role in the pathogenesis of occlusive vascular diseases. Activation of vitamin D receptors (VDR) elicits both growth-inhibitory and anti-inflammatory effects. Here, we investigated the expression of TNF-α and VDR in post-angioplasty coronary artery neointimal lesions of hypercholesterolemic swine and examined the effect of vitamin D deficiency on the development of coronary restenosis. We also examined the effect of calcitriol on cell proliferation and effect of TNF-α on VDR activity and expression in porcine coronary artery smooth muscle cells (PCASMCs) in-vitro.

Methodology/Principal Findings

Expression of VDR and TNF-α and the effect of vitamin D deficiency in post-angioplasty coronary arteries were analyzed by immunohistochemistry and histomorphometry. Cell proliferation was examined by thymidine and BrdU incorporation assays in cultured PCASMCs. Effect of TNF-α-stimulation on the activity and expression of VDR was analyzed by luciferase assay, immunoblotting and immunocytochemistry. In-vivo, morphometric analysis of the tissues revealed typical lesions with significant neointimal proliferation. Histological evaluation showed expression of smooth muscle α-actin and significantly increased expression of TNF-α in neointimal lesions. Interestingly, there was significantly decreased expression of VDR in PCASMCs of neointimal region compared to normal media. Indeed, post-balloon angioplasty restenosis was significantly higher in vitamin D-deficient hypercholesterolemic swine compared to vitamin D-sufficient group. In-vitro, calcitriol inhibited both serum- and PDGF-BB-induced proliferation in PCASMCs and TNF-α-stimulation significantly decreased the expression and activity of VDR in PCASMCs.

Conclusions/Significance

These data suggest that significant downregulation of VDR in proliferating smooth muscle cells in neointimal lesions could be due to atherogenic cytokines, including TNF-α. Vitamin D deficiency potentiates the development of coronary restenosis. Calcitriol has anti-proliferative properties in PCASMCs and these actions are mediated through VDR. This could be a potential mechanism for uncontrolled growth of neointimal cells in injured arteries leading to restenosis.     

间断切口与长切口获取大隐静脉在冠状动脉旁路移植术中作用的对比研究

目的:比较冠状动脉旁路移植术(CABG)中采用间断切口与长切口获取大隐静脉作为静脉桥材料的优缺点。方法:选择2011年12月至2012年12月宁夏医科大学总医院心脏大血管外科111例行CABG的冠状动脉粥样硬化性心脏病患者为研究对象。根据术中获取大隐静脉方法的不同,随机将其分为两组,长切口组64例,在CABG中采用长切口法获取大隐静脉,间断切口组47例,在CABG中采用间断切口法获取大隐静脉。比较两组大隐静脉获取时间、下肢切口缝合时间、下肢手术时间、大隐静脉桥长度、下肢切口长度和下肢切口并发症发生率的差异。结果:间断切口组大隐静脉桥长度及下肢手术时间(45.4±6.7)cm,(65.8±10.3)min与长切口组(47.5±6.7)cm,(65.8±10.3)min比较无统计学差异(P0.05)。间断切口组获取大隐静脉的时间(48.9±8.3)min显著长于长切口组(37.3±5.8)min,下肢切口长度与缝合时间(17.0±3.5)cm,(16.9±3.4)min明显短于长切口组的(43.5±6.4)min,(31.7±5.9)min,差异均有统计学意义(P0.05)。两组大隐静脉壁的损伤情况比较无统计学差异(P0.05),但间断切口组术后下肢切口延迟愈合、感染、渗出、下肢血肿等并发症的发生率低于长切口组(P0.05)。结论:在冠状动脉旁路移植术中,间断切口获取大隐静脉能够显著缩短下肢手术切口长度,有助于减少术后下肢切口感染、延迟愈合、渗出、下肢血肿等并发症的发生。     

冠状动脉旁路移植术后大隐静脉桥再狭窄机制

冠状动脉旁路移植术是冠状动脉粥样硬化性心脏病的常规治疗方法之一.动脉血管作为移植血管材料有其自身优势,但对大多数患者而言,自体大隐静脉仍然是最常用的移植血管材料.新内膜形成和粥样硬化导致的静脉桥再狭窄已成为一个亟待解决的问题.目前认为静脉桥再狭窄的病理机制包括:早期桥血管闭塞,主要由于急性血栓形成;中期血管闭塞,主要由于血管内膜纤维化增生;晚期闭塞,主要由于静脉粥样硬化.     

Endothelial Cells of Atherosclerotic Coronary Arteries in vivo Obtained during Angioplasty (Intravascular Biopsy)

The relevance of our study is due to the unresolved problem of atherosclerosis, a disease that causes a greatest many disabilities and deaths. A definite value in its initiation, progression, and destabilization is assigned to endothelial cells, which are prone to pathological effects of various factors. In patients with atherosclerosis, it is impossible to obtain endothelial cells in vivo and in situ and, accordingly, to characterize their cytological features. Endothelial biopsy in this work was performed by coronary angioplasty in 64 patients with various clinical forms of coronary heart disease. A balloon catheter was used as a probe for biopsy. Preparations of endothelial biopsy were prepared using the principles of liquid-based cytology. Anucleated, polygonal cells with nuclei and their clusters, as well as apoptotic bodies with the immunophenotype CD31⁺, CD34⁺, CD105^+/–, PanCk^+/–, CD45^–, and CD68^–, have been obtained. It is confirmed that they belong to the endothelium, which shows that further cytological studies can be carried out with the purpose of evaluating the etiology and pathogenesis of atherosclerotic processes.     

Exploring the Binding Nature of Pyrrolidine Pocket-Dependent Interactions in the Polo-Box Domain of Polo-Like Kinase 1

Background

Over the years, a great deal of effort has been focused on the design and synthesis of potent, linear peptide inhibitors targeting the polo-like kinase 1 (Plk1), which is critically involved in multiple mitotic processes and has been established as an adverse prognostic marker for tumor patients. Plk1 localizes to its intracellular anchoring sites via its polo-box domain, and inhibiting the Plk1 polo-box domain has been considered as an approach to circumvent the specificity problems associated with inhibiting the conserved adenosine triphosphate-binding pocket. The polo-box domain consists of two different binding regions, such as the unique, broader pyrrolidine-binding pocket and the conserved, narrow, Tyr-rich hydrophobic channel, among the three Plk polo-box domains (Plks 1–3), respectively. Therefore, the studies that provide insights into the binding nature of the unique, broader pyrrolidine-binding pocket might lead to the development of selective Plk1-inhibitory compounds.

Methodology/Principal Findings

In an attempt to retain the monospecificity by targeting the unique, broader pyrrolidine-binding pocket, here, for the first time, a systematic approach was undertaken to examine the structure-activity relationship of N-terminal-truncated PLHSpTM derivatives, to apply a site-directed ligand approach using bulky aromatic and non-aromatic systems, and to characterize the binding nature of these analogues using X-ray crystallographic studies. We have identified a new mode of binding interactions, having improved binding affinity and retaining the Plk1 polo-box domain specificity, at the pyrrolidine-binding pocket. Furthermore, our data revealed that the pyrrolidine-binding pocket was very specific to recognize a short and bulky hydrophobic ligand like adamantane, whereas the Tyr-rich hydrophobic channel was specific with lengthy and small hydrophobic groups.

Conclusion/Significance

The progress made using our site-directed ligands validated this approach to specifically direct the ligand into the unique pyrrolidine-binding region, and it extends the applicability of the strategy for discovering selective protein-protein interaction inhibitors.     

Use of Pulmonary Artery Catheter in Coronary Artery Bypass Graft. Costs and Long-Term Outcomes

BackgroundPulmonary artery catheters (PAC) are used widely to monitor hemodynamics in patients undergoing coronary bypass graft (CABG) surgery. However, recent studies have raised concerns regarding both the effectiveness and safety of PAC. Therefore, our aim was to determine the effects of the use of PAC on the short- and long-term health and economic outcomes of patients undergoing CABG.Methods1361 Chinese patients who consecutively underwent isolated, primary CABG at the Cardiovascular Institute of Fuwai Hospital from June 1, 2012 to December 31, 2012 were included in this study. Of all the patients, 453 received PAC during operation (PAC group) and 908 received no PAC therapy (control group). Short-term and long-term mortality and major complications were analyzed with multivariate regression analysis and propensity score matched-pair analysis was used to yield two well-matched groups for further comparison.ResultsThe patients who were managed with PAC more often received intraoperative vasoactive drugs dopamine (70.9% vs. 45.5%; P<0.001) and epinephrine (7.7% vs. 2.6%; P<0.001). In addition, costs for initial hospitalization were higher for PAC patients ($14,535 vs. $13,873, respectively, p = 0.004). PAC use was neither associated with the perioperative mortality or major complications, nor was it associated with long-term mortality and major adverse cardiac and cerebrovascular events. In addition, comparison between two well-matched groups showed no significant differences either in baseline characteristics or in short-term and long-term outcomes.ConclusionsThere is no clear indication of any benefit or harm in managing CABG patients with PAC. However, use of PAC in CABG is more expensive. That is, PAC use increased costs without benefit and thus appears unjustified for routine use in CABG surgery.     

Increased CSF Levels of Phosphorylated Neurofilament Heavy Protein following Bout in Amateur Boxers

Introduction

Diagnosis of mild TBI is hampered by the lack of imaging or biochemical measurements for identifying or quantifying mild TBI in a clinical setting. We have previously shown increased biomarker levels of protein reflecting axonal (neurofilament light protein and tau) and glial (GFAP and S-100B) damage in cerebrospinal fluid (CSF) after a boxing bout. The aims of this study were to find other biomarkers of mild TBI, which may help clinicians diagnose and monitor mild TBI, and to calculate the role of APOE ε4 allele genotype which has been associated with poor outcome after TBI.

Materials and Methods

Thirty amateur boxers with a minimum of 45 bouts and 25 non-boxing matched controls were included in a prospective cohort study. CSF and blood were collected at one occasion between 1 and 6 days after a bout, and after a rest period for at least 14 days (follow up). The controls were tested once. CSF levels of neurofilament heavy (pNFH), amyloid precursor proteins (sAPPα and sAPPβ), ApoE and ApoA1 were analyzed. In blood, plasma levels of Aβ42 and ApoE genotype were analyzed.

Results

CSF levels of pNFH were significantly increased between 1 and 6 days after boxing as compared with controls (p<0.001). The concentrations decreased at follow up but were still significantly increased compared to controls (p = 0.018). CSF pNFH concentrations correlated with NFL (r =  0.57 after bout and 0.64 at follow up, p<0.001). No significant change was found in the other biomarkers, as compared to controls. Boxers carrying the APOE ε4 allele had similar biomarker concentrations as non-carriers.

Conclusions

Subconcussive repetitive trauma in amateur boxing causes a mild TBI that may be diagnosed by CSF analysis of pNFH, even without unconsciousness or concussion symptoms. Possession of the APOE ε4 allele was not found to influence biomarker levels after acute TBI.     

冠状动脉旁路移植患者围术期的BNP 水平变化及临床意义

目的:研究冠状动脉旁路移植手术后患者B型脑钠钛(BNP)水平变化规律及临床意义。方法:选取我院2014年6月到2015年6月间收治的冠状动脉旁路移植手术患者80名,根据患者心脏左心室射血分数(LVEF)分为A组(45%)和B组(≤45%),观察两组患者在不同时间的BNP水平,对比两患临床相关指标、及心房颤抖和心功能不全发生情况。结果:A组患者在血管活性物质使用量、呼吸机使用时间、监护室停留时间及心房颤抖和心功能不全发生率都明显小于B组,差异有统计学意义(P0.05);术后6h两组患者的BNP水平开始明显上升,在术后24h达到峰值,此后开始下降但仍维持较高水平,组内比较差异均有统计学意义(P0.05)。A组患者在术前及术后各个时间段内BNP水平均明显小于B组,组间比较比较均有统计学意义(P0.05)。结论:冠状动脉旁路移植患者围手术期BNP水平可以反应患者心脏功能状况,BNP水平越高表示患者心脏越差。     

Coronary Injury Score Correlates with Proliferating Cells and Alpha-Smooth Muscle Actin Expression in Stented Porcine Coronary Arteries

Neointimal formation and cell proliferation resulting into in-stent restenosis is a major pathophysiological event following the deployment of stents in the coronary arteries. In this study, we assessed the degree of injury, based on damage to internal elastic lamina, media, external elastic lamina, and adventitia following the intravascular stenting, and its relationship with the degree of smooth muscle cell proliferation. We examined the smooth muscle cell proliferation and their phenotype at different levels of stent injury in the coronary arteries of domestic swine fed a normal swine diet. Five weeks after stent implantation, swine with and without stents were euthanized and coronaries were excised. Arteries were embedded in methyl methacrylate and sections were stained with H&E, trichrome, and Movat’s pentachrome. The expression of Ki67, α-smooth muscle actin (SMA), vimentin, and HMGB1 was evaluated by immunofluorescence. There was a positive correlation between percent area stenosis and injury score. The distribution of SMA and vimentin was correlated with the degree of arterial injury such that arteries that had an injury score >2 did not have immunoreactivity to SMA in the neointimal cells near the stent struts, but these neointimal cells were positive for vimentin, suggesting a change in the smooth muscle cell phenotype. The Ki67 and HMGB1 immunoreactivity was highly correlated with the fragmentation of the IEL and injury in the tunica media. Thus, the extent of coronary arterial injury during interventional procedure will dictate the degree of neointimal hyperplasia, in-stent restenosis, and smooth muscle cell phenotype.     

乳腺浸润性导管癌组织IRS1、PRSS3蛋白表达与磷酸化蛋白激酶B表达和预后的关系研究

摘要 目的：探讨乳腺浸润性导管癌（BIDC）组织胰岛素受体底物1（IRS1）蛋白、丝氨酸蛋白酶3（PRSS3）蛋白表达与磷酸化蛋白激酶B（p-AKT）表达以及预后的关系。方法：选择2017年1月至2018年12月我院收治的363例BIDC患者,采用免疫组化法检测经手术切除的BIDC癌组织和癌旁组织中IRS1蛋白、PRSS3蛋白以及p-AKT表达,比较BIDC不同病理特征IRS1蛋白、PRSS3蛋白表达差异。Spearman秩相关分析IRS1蛋白、PRSS3蛋白表达与p-AKT表达的相关性。术后定期随访,采用Kaplan-Meier生存分析、Cox风险比例回归分析IRS1蛋白、PRSS3蛋白表达与BIDC患者预后的关系。结果：BIDC组织中IRS1蛋白、PRSS3蛋白、p-AKT阳性表达率分别为68.87%、58.13%、68.04%,均高于对照组的46.56%、40.50%、41.60%（P＜0.05）。IRS1蛋白表达、PRSS3蛋白表达与p-AKT表达均呈正相关（rs=0.805、0.796,P＜0.05）。肿瘤直径＞2 cm、低中度分化、AJCC分期为Ⅱ期的患者IRS1蛋白阳性表达率高于肿瘤直径≤2cm、高度分化、AJCC分期为Ⅰ期的患者（P＜0.05）,AJCC分期为Ⅱ期、HER-2阳性表达、Ki-67阳性表达的患者PRSS3蛋白阳性表达率高于AJCC分期为Ⅰ期、HER-2阴性表达、Ki-67阴性表达的患者（P＜0.05）。Kaplan-Meier生存分析显示IRS1蛋白、PRSS3蛋白阳性表达者PFS生存率、OS生存率低于IRS1蛋白、PRSS3蛋白阴性表达者（P＜0.05）。多因素COX风险比例回归结果显示AJCC分期Ⅲ期、IRS1蛋白阳性表达、PRSS3蛋白阳性表达是BIDC患者预后不良的危险因素（P＜0.05）。结论：BIDC癌组织中IRS1蛋白、PRSS3蛋白阳性表达率增高,IRS1蛋白、PRSS3蛋白可能通过调节p-AKT参与BIDC癌症进展过程。     

磷酸化组蛋白H3在小麦有丝分裂与减数分裂中的分布

在细胞周期中 ,与染色质凝集偶联的一类组蛋白修饰是组蛋白H3的磷酸化。运用H3_Ser 10磷酸化的特异性抗体 ,通过间接免疫荧光标记检测了磷酸化组蛋白H3在小麦 (TriticumaestivumL .)有丝分裂与减数分裂细胞中的分布。有丝分裂时 ,H3磷酸化起始于早前期 ,消失于末期 ,在中期与后期 ,H3磷酸化主要分布在着丝粒两侧的异染色质区。减数分裂时 ,H3磷酸化起始于细线期向偶线期转换时 ,并且从前期Ⅰ到后期Ⅰ保持均一分布于整个染色体上 ,直到末期Ⅰ消失 ,而中期Ⅱ与后期Ⅱ在着丝粒两侧的异染色质区的信号略强于染色体臂 ,直至消失于末期Ⅱ。磷酸化组蛋白H3在两类细胞分裂中的不同分布暗示这种保守的翻译后修饰可能发挥着除参与染色体凝集外的更复杂的作用。     

磷酸化组蛋白H3在小麦有丝分裂与减数分裂中的分布

在细胞周期中, 与染色质凝集偶联的一类组蛋白修饰是组蛋白H3的磷酸化.运用H3-Ser 10磷酸化的特异性抗体,通过间接免疫荧光标记检测了磷酸化组蛋白H3在小麦(Triticum aestivum L.)有丝分裂与减数分裂细胞中的分布.有丝分裂时,H3磷酸化起始于早前期,消失于末期,在中期与后期,H3磷酸化主要分布在着丝粒两侧的异染色质区.减数分裂时,H3磷酸化起始于细线期向偶线期转换时,并且从前期Ⅰ到后期Ⅰ保持均一分布于整个染色体上,直到末期Ⅰ消失,而中期Ⅱ与后期Ⅱ在着丝粒两侧的异染色质区的信号略强于染色体臂,直至消失于末期Ⅱ.磷酸化组蛋白H3在两类细胞分裂中的不同分布暗示这种保守的翻译后修饰可能发挥着除参与染色体凝集外的更复杂的作用.     

Structure-Bioactivity Relationship for Benzimidazole Thiophene Inhibitors of Polo-Like Kinase 1 (PLK1), a Potential Drug Target in Schistosoma mansoni

Background

Schistosoma flatworm parasites cause schistosomiasis, a chronic and debilitating disease of poverty in developing countries. Praziquantel is employed for treatment and disease control. However, its efficacy spectrum is incomplete (less active or inactive against immature stages of the parasite) and there is a concern of drug resistance. Thus, there is a need to identify new drugs and drug targets.

Methodology/Principal Findings

We show that RNA interference (RNAi) of the Schistosoma mansoni ortholog of human polo-like kinase (huPLK)1 elicits a deleterious phenotypic alteration in post-infective larvae (schistosomula or somules). Phenotypic screening and analysis of schistosomula and adult S. mansoni with small molecule inhibitors of huPLK1 identified a number of potent anti-schistosomals. Among these was a GlaxoSmithKline (GSK) benzimidazole thiophene inhibitor that has completed Phase I clinical trials for treatment of solid tumor malignancies. We then obtained GSKs Published Kinase Inhibitor Sets (PKIS) 1 and 2, and phenotypically screened an expanded series of 38 benzimidazole thiophene PLK1 inhibitors. Computational analysis of controls and PLK1 inhibitor-treated populations of somules demonstrated a distinctive phenotype distribution. Using principal component analysis (PCA), the phenotypes exhibited by these populations were mapped, visualized and analyzed through projection to a low-dimensional space. The phenotype distribution was found to have a distinct shape and topology, which could be elicited using cluster analysis. A structure-activity relationship (SAR) was identified for the benzimidazole thiophenes that held for both somules and adult parasites. The most potent inhibitors produced marked phenotypic alterations at 1–2 μM within 1 h. Among these were compounds previously characterized as potent inhibitors of huPLK1 in cell assays.

Conclusions/Significance

The reverse genetic and chemical SAR data support a continued investigation of SmPLK1 as a possible drug target and/or the prosecution of the benzimidazole thiophene chemotype as a source of novel anti-schistosomals.