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31.
Matthias Barone Matthias Müller Slim Chiha Jiang Ren Dominik Albat Arne Soicke Stephan Dohmen Marco Klein Judith Bruns Maarten van Dinther Robert Opitz Peter Lindemann Monika Beerbaum Kathrin Motzny Yvette Roske Peter Schmieder Rudolf Volkmer Marc Nazar Udo Heinemann Hartmut Oschkinat Peter ten Dijke Hans-Günther Schmalz Ronald Kühne 《Proceedings of the National Academy of Sciences of the United States of America》2020,117(47):29684
Battling metastasis through inhibition of cell motility is considered a promising approach to support cancer therapies. In this context, Ena/VASP-depending signaling pathways, in particular interactions with their EVH1 domains, are promising targets for pharmaceutical intervention. However, protein–protein interactions involving proline-rich segments are notoriously difficult to address by small molecules. Hence, structure-based design efforts in combination with the chemical synthesis of additional molecular entities are required. Building on a previously developed nonpeptidic micromolar inhibitor, we determined 22 crystal structures of ENAH EVH1 in complex with inhibitors and rationally extended our library of conformationally defined proline-derived modules (ProMs) to succeed in developing a nanomolar inhibitor ( Da). In contrast to the previous inhibitor, the optimized compounds reduced extravasation of invasive breast cancer cells in a zebrafish model. This study represents an example of successful, structure-guided development of low molecular weight inhibitors specifically and selectively addressing a proline-rich sequence-recognizing domain that is characterized by a shallow epitope lacking defined binding pockets. The evolved high-affinity inhibitor may now serve as a tool in validating the basic therapeutic concept, i.e., the suppression of cancer metastasis by inhibiting a crucial protein–protein interaction involved in actin filament processing and cell migration.Metastasis is a complex multistep process (1, 2) employing, among others, mechanisms governing actin cytoskeleton dynamics involving integrin signaling and actin regulatory proteins (3–5). So far, all approved antimetastatic drugs antagonize integrins (6) or inhibit downstream kinases (7, 8) (SI Appendix, Fig. S1). In the metastatic setting however, these drugs appear to have only limited success (9–13) and 5-y survival is not increasing satisfactorily (14, 15), making new approaches in antimetastatic drug development essential to meet this urgent medical need.The enabled/vasodilator stimulated phosphoprotein protein family (Ena/VASP) acts as a crucial hub in cell migration by linking actin filaments to invadopodia and focal adhesions (16–22). Due to their role in the transformation of benign lesions into invasive and metastatic cancer, Ena/VASP proteins are discussed as part of the invasive signature and as a marker of breast carcinogenesis (23–25). At the advanced tumor stage, the protein family is overexpressed (26–28), which has been shown to increase migration speed in vivo (29) and to potentiate invasiveness (30). Yet, no sufficiently potent probes to interfere with Ena/VASP in vivo have been reported.The three vertebrate Ena/VASP family members, enabled homolog (ENAH), VASP, and Ena-VASP-like (EVL), share a tripartite structural organization in which two Ena/VASP homology domains (EVH1 and EVH2) are separated by a more divergent proline-rich central part. Interactions of the EVH2 domain are involved in the elongation and protection of barbed-end actin filaments from capping proteins and tetramerization (31, 32). EVH1 folds into a structured globular domain that interacts with proteins at focal adhesions (33), the leading edge (34, 35), and invadopodia (36, 37) by recognizing the motif [F/W/L/Y]PxP (35, 38) ( hydrophobic, x any; SI Appendix, Fig. S3) in poly-L-proline type II helix (PPII) conformation.In the course of our research into small molecules as potential inhibitors of protein–protein interactions (39) we recently in silico designed and stereo-selectively synthesized scaffolds, coined ProMs, which mimic pairs of prolines in PPII conformation (40). The modular combination of different ProMs thereby allowed us to generate nonpeptidic secondary-structure mimetics that fulfill the steric requirements of the addressed proline-rich motif-recognizing domain (41–47). For the EVH1 domain, our proof-of-concept study yielded a canonically binding, nontoxic, cell-membrane-permeable, 706-Da inhibitor 1 (Fig. 1A) composed of two different ProM scaffolds and 2-chloro-(L)-phenylalanine (2-Cl-Phe) (40). While the synthetic inhibitor 1 represents the compound with the highest reported affinity toward Ena/VASP EVH1 domains, a further improvement was required for in vivo experiments. Here we report successful structure-based optimization of inhibitor 1 based on 22 high-resolution crystal structures of ENAH EVH1 in complex with different inhibitors (SI Appendix, Tables S1–S6), including the well-resolved C-terminal binding epitope TEDEL of ActA from Listeria monocytogenes (48). Newly identified interaction sites adjacent to the C terminus of 1 were addressed by in silico designed and stereo-selectively synthesized modifications of the ProM-1 scaffold (Fig. 1A). While drastically increasing the affinity against a rather flat protein surface we conserved structural simplicity, low molecular weight, nontoxicity, and cell-membrane permeability. Potent compounds against Ena/VASP were shown to also act in vivo, i.e., by inhibiting cancer cell extravasation in zebrafish at only 1 M, thereby paving the way for future preclinical studies.Open in a separate windowFig. 1.(A) Structure of the first-generation Ena/VASP EVH1 inhibitor 1. All compositions share the N-acetylated 2-chloro-phenylalanine unit (blue) attached to a central ProM-2 scaffold (red). Esterification of the C terminus renders the inhibitors cell-membrane permeable (40). (B) General (modular) architecture of nonpeptidic, conformationally preorganized inhibitors used in this study. Structural variation (pink) was achieved by replacing the C-terminal ProM-1 unit (green) by ProM-9, ProM-13, ProM-12, ProM-15, or ProM-17 (Table 1). 相似文献
32.
Slim Charfi Ahmad Sellami Abdellatif Affes Khalil Yaïch Rafik Mzali Tahya Sellami Boudawara 《International journal of colorectal disease》2014,29(8):1009-1012
Purpose
Appendicitis is by far the commonest major emergency general surgical operation. Histopathological examination of the appendix is routinely performed.Methods
This study is a retrospective analysis of 24,697 appendectomies performed from January 2003 to December 2011. Pathological reports were analyzed for the following parameters: age, gender, and pathological diagnosis.Results
Appendectomy specimens represent 17 % of all pathological reports. Acute appendicitis was present in 19,637 (79.5 %) patients. The perforation rate was 6.3 % and was significantly higher in adult patients. The negative appendectomy rate was 15 % and was significantly higher in female and adult patients. The incidence of negative appendectomies had clearly decreased over the 9-year period distribution. Incidental unexpected pathological diagnoses were noted in 226 (0.9 %) appendectomy specimens. Neoplastic lesions were present in 171 cases (0.7 %); they include carcinoid, adenocarcinoma, and mucinous neoplasms.Conclusions
Routine pathological examination of appendectomy specimens is expensive. With advances in technology and imaging modalities, the diagnosis of acute appendicitis has improved, with a subsequent significant reduction in negative appendectomy. There are still a number of unusual diagnoses found in appendicectomy specimens supporting the continued use of routine histology. 相似文献33.
34.
35.
Chrysosporum ovalisporum is a cylindrospermopsin toxin producing cyanobacterium that was reported in several lakes and reservoirs. Its growth dynamics and toxin distribution in field remain largely undocumented. Chrysosporum ovalisporum was reported in 2009 in Karaoun Reservoir, Lebanon. We investigated the factors controlling the occurrence of this cyanobacterium and vertical distribution of cylindrospermopsin in Karaoun Reservoir. We conducted bi-weekly sampling campaigns between May 2012 and August 2013. Results showed that Chrysosporum ovalisporum is an ecologically plastic species that was observed in all seasons. Unlike the high temperatures, above 26 °C, which is associated with blooms of Chrysosporum ovalisporum in Lakes Kinneret (Israel), Lisimachia and Trichonis (Greece) and Arcos Reservoir (Spain), Chrysosporum ovalisporum in Karaoun Reservoir bloomed in October 2012 at a water temperature of 22 °C during weak stratification. Cylindrospermopsin was detected in almost all water samples even when Chrysosporum ovalisporum was not detected. Chrysosporum ovalisporum biovolumes and cylindrospermopsin concentrations were not correlated (n = 31, r2 = −0.05). Cylindrospermopsin reached a maximum concentration of 1.7 µg L−1. The vertical profiles of toxin concentrations suggested its possible degradation or sedimentation resulting in its disappearance from the water column. The field growth conditions of Chrysosporum ovalisporum in this study revealed that it can bloom at the subsurface water temperature of 22 °C increasing the risk of its development and expansion in lakes located in temperate climate regions. 相似文献
36.
Liver transplantation for hepatocellular cancer: should the current indication criteria be changed? 总被引:11,自引:0,他引:11
Luciano?De?CarlisEmail author Alessandro?Giacomoni Andrea?Lauterio Abdallah?Slim Cinzia?Sammartino Vincenzo?Pirotta Giovanni?Colella Domenico?Forti 《Transplant international》2003,16(2):115-122
Liver transplantation (LTx) is the best treatment for hepatocellular carcinoma (HCC), but should be offered only to selected patients. The usual procedure is to transplant only for small and unilobular tumors. The aim of this paper is to verify whether the actual indication criteria are still justified. The details of 121 patients with HCC who were submitted to LTx from 1985 to 2000 were analyzed. Age, gender, liver disease, Child class, alpha-fetoprotein (AFP) level, presence of tumor capsule, vascular invasion, size and number of nodules, histological grade, and pTNM were considered. The 5- and 10-year actuarial survival rates were 61.7% and 53.1%. Freedom from recurrence was 85.9% and 85.9%, respectively. At univariate analysis, size, presence of capsule, AFP levels, vascular invasion, grade, pTNM, transarterial chemoembolization (TACE), Child class, and age were all significantly related to survival and/or cancer recurrence. Presence of capsule, AFP levels, and viral cirrhosis were independent variables in Cox's analysis for survival, whereas histological grade, AFP levels, and vascular invasion were significant independent variables for recurrence. In conclusion, a strict selection should be made to optimize graft allocation while size and multifocality should probably no longer be considered a contraindication for LTx. Histological grade, AFP levels, and vascular invasion, as indicator of tumor behavior, more likely reflect the risk of recurrence. 相似文献
37.
Coronary computed tomography angiography (CTA) is a highly accurate noninvasive test that is increasingly used in symptomatic patients primarily for the diagnosis of coronary artery disease (CAD). Beyond its proven accuracy, data have now clearly demonstrated the incremental prognostic information available from coronary CTA related to the presence, extent, and severity of obstructive and nonobstructive CAD across a variety of clinical settings and patient populations. Current evidence supports the use of coronary CTA not only for the diagnosis of CAD in appropriately selected symptomatic patients but also to further refine their cardiovascular risk assessment following testing. 相似文献
38.
39.
Omar F. Khabour Enas S. Alsatari Mohammad Azab Karem H. Alzoubi May F. Sadiq 《Environmental and molecular mutagenesis》2011,52(3):224-228
Tobacco smoking is a major world health problem. Recently, waterpipe smoking has become more popular in many countries. Although the genotoxicity associated with cigarette smoking has been extensively investigated, studies evaluating such toxicity in waterpipe users are still lacking. In this study, we examined the genotoxicity of waterpipe smoking in lymphocytes compared with the genotoxicity of cigarette smoking. Genotoxicity was evaluated using the sister chromatid exchanges (SCEs) assay. Fifty waterpipe smokers and 18 healthy nonsmokers participated in this study. Additionally, 18 heavy cigarette smokers (CS) were recruited for comparison. The results show that waterpipe smoking and cigarette smoking significantly increase the frequencies of SCEs (P < 0.01) compared with those of nonsmokers, indicating the genotoxic effect of tobacco smoking. In addition, frequencies of SCEs were significantly higher among waterpipe smokers compared with CS (P < 0.01), indicating that waterpipe smoking is more genotoxic than cigarette smoking. Moreover, the frequency of SCEs increased with the extent of waterpipe use. In conclusion, waterpipe smoking is genotoxic to lymphocytes and the magnitude of its genotoxicity is higher than that induced by regular cigarette smoking. Environ. Mol. Mutagen., 2011. © 2010 Wiley‐Liss, Inc. 相似文献
40.