scholarly journals Tamoxifen Derivatives Alter Retromer-Dependent Endosomal Tubulation and Sorting to Block Retrograde Trafficking of Shiga Toxins

Toxins ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 424
Author(s):  
Andrey S. Selyunin ◽  
Karinel Nieves-Merced ◽  
Danyang Li ◽  
Stanton F. McHardy ◽  
Somshuvra Mukhopadhyay
Keyword(s):  
Chemical Nature ◽  
Inhibitory Effect ◽  
Chemotherapeutic Drug ◽  
Shiga Toxins ◽  
Retrograde Trafficking ◽  
Receptor Modulator ◽  
Golgi Transport ◽  
Structure Activity ◽  
Measurable Activity ◽  
Basic Amine

Shiga toxin 1 and 2 (STx1 and STx2) undergo retrograde trafficking to reach the cytosol of cells where they target ribosomes. As retrograde trafficking is essential for disease, inhibiting STx1/STx2 trafficking is therapeutically promising. Recently, we discovered that the chemotherapeutic drug tamoxifen potently inhibits the trafficking of STx1/STx2 at the critical early endosome-to-Golgi step. We further reported that the activity of tamoxifen against STx1/STx2 is independent of its selective estrogen receptor modulator (SERM) property and instead depends on its weakly basic chemical nature, which allows tamoxifen to increase endolysosomal pH and alter the recruitment of retromer to endosomes. The goal of the current work was to obtain a better understanding of the mechanism of action of tamoxifen against the more disease-relevant toxin STx2, and to differentiate between the roles of changes in endolysosomal pH and retromer function. Structure activity relationship (SAR) analyses revealed that a weakly basic amine group was essential for anti-STx2 activity. However, ability to deacidify endolysosomes was not obligatorily necessary because a tamoxifen derivative that did not increase endolysosomal pH exerted reduced, but measurable, activity. Additional assays demonstrated that protective derivatives inhibited the formation of retromer-dependent, Golgi-directed, endosomal tubules, which mediate endosome-to-Golgi transport, and the sorting of STx2 into these tubules. These results identify retromer-mediated endosomal tubulation and sorting to be fundamental processes impacted by tamoxifen; provide an explanation for the inhibitory effect of tamoxifen on STx2; and have important implications for the therapeutic use of tamoxifen, including its development for treating Shiga toxicosis.

scholarly journals Ten Representative Saponins on Tissue Factor Expression in Human Monocytes: Structure–Activity Relationships and Molecular Docking

2020 ◽  
Vol 15 (3) ◽  
pp. 1934578X2091368
Author(s):  
Yongjiang Zeng ◽  
Xuhua He ◽  
Wenwen Jiang ◽  
Junping Kou ◽  
Boyang Yu
Keyword(s):  
Cardiovascular Disease ◽  
Molecular Docking ◽  
Tissue Factor ◽  
Inhibitory Effect ◽  
Coagulation Cascade ◽  
Human Monocytes ◽  
Messenger Ribonucleic Acid ◽  
Structure Activity Relationships ◽  
Protein Levels ◽  
Structure Activity

Saponins have significant bioactivities in treating cardiovascular disease. Whereas there is a lack of in-depth knowledge about how saponins prevent cardiovascular disease. Tissue factor (TF) is the major initiator of the coagulation cascade and plays an important role in hemostasis and thrombosis. However structure–activity relationships (SARs) of saponins inhibiting TF activity have not been discussed in detail at present. To further clarify the relationships between saponins and TF, in this study, 10 representative saponins were selected to study the inhibitory effect on TF procoagulant activity of monocytes by an improved chromogenic substrate method, and the possible SARs were preliminarily analyzed. Furthermore, molecular docking analysis suggested that 4 representative saponins had a good affinity with TF/FVIIa. In addition, a representative saponin, ruscogenin, decreased both messenger ribonucleic acid and protein levels of TF in human monocytes partly due to its downregulation of nuclear factor kappa-light-chain-enhancer of activated B cells and c-Jun N-terminal kinase pathways. In conclusion, this study provides further explanation for the cardiovascular protection of saponins, and the analysis of SARs between inhibiting TF activity and saponins will be helpful to explore the therapeutic TF inhibitors.

scholarly journals Design and Synthesis of Various 5′-Deoxy-5′-(4-Substituted-1,2,3-Triazol-1-yl)-Uridine Analogues as Inhibitors of Mycobacterium tuberculosis Mur Ligases

Molecules ◽  
2020 ◽  
Vol 25 (21) ◽  
pp. 4953
Author(s):  
Vincent Hervin ◽  
Ritu Arora ◽  
Jyoti Rani ◽  
Srinivasan Ramchandran ◽  
Urmi Bajpai ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Molecular Docking ◽  
Active Site ◽  
Inhibitory Effect ◽  
Natural Substrate ◽  
Screening Assay ◽  
One Pot ◽  
Peptidoglycan Biosynthesis ◽  
Design And Synthesis ◽  
Structure Activity

The synthesis of hitherto unknown 5′-deoxy-5′-(4-substituted-1,2,3-triazol-1-yl)-uridine and its evaluation, through an one-pot screening assay, against MurA-F enzymes involved in Mycobacterium tuberculosis (Mtb), are described. Starting from UDP-N-acetylmuramic acid (UDP-MurNAc), the natural substrate involved in the peptidoglycan biosynthesis, our strategy was to substitute the diphosphate group of UDP-MurNAc by a 1,2,3-triazolo spacer under copper-catalyzed azide-alkyne cycloaddition conditions. The structure-activity relationship was discussed and among the 23 novel compounds developed, N-acetylglucosamine analogues 11c and 11e emerged as the best inhibitors against the Mtb MurA-F enzymes reconstruction pathway with an inhibitory effect of 56% and 50%, respectively, at 100 μM. Both compounds are selective inhibitors of Mtb MurE, the molecular docking and molecular dynamic simulation suggesting that 11c and 11e are occupying the active site of Mtb MurE ligase.

Inhibitory effect and structure–activity relationship of some Biginelli-type pyrimidines against HSV-1

2012 ◽  
Vol 22 (3) ◽  
pp. 1270-1276 ◽  
Author(s):  
Rezvan Zabihollahi ◽  
Afshin Fassihi ◽  
Mohamad Reza Aghasadeghi ◽  
Hamid Reza Memarian ◽  
Mohammad Soleimani ◽  
...  
Keyword(s):  
Structure Activity Relationship ◽  
Inhibitory Effect ◽  
Activity Relationship ◽  
Structure Activity ◽  
Relationship Of ◽  
Hsv 1

scholarly journals Structure-Activity Relationship Studies of Retro-1 Analogues Against Shiga Toxin

2020 ◽  
Author(s):  
Hajer Abdelkafi ◽  
Aurélien Michau ◽  
Valérie Pons ◽  
Flora Ngadjeua ◽  
Alexandra Clerget ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Shiga Toxin ◽  
Intracellular Trafficking ◽  
High Throughput Screening ◽  
Cell Protein ◽  
Shiga Toxins ◽  
Structure Activity ◽  
Early Endosomes ◽  
A Cell ◽  
Sar Study

<p>The Retro-1 molecule was identified in a high-throughput screening as an inhibitor of ricin and Shiga toxins by diminishing their intracellular trafficking <i>via</i> the retrograde route, from early endosomes to the Golgi apparatus. In order to improve the activity of Retro-1, a SAR study was undertaken yielding an analog that possesses roughly 70-fold better EC<sub>50</sub> against Shiga toxin cytotoxicity measured in a cell protein synthesis assay. </p>

scholarly journals Anticancer and Structure Activity Relationship of Non-Symmetrical Choline Kinase Inhibitors

Pharmaceutics ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1360
Author(s):  
Santiago Schiaffino-Ortega ◽  
Elena Mariotto ◽  
Pilar María Luque-Navarro ◽  
María Kimatrai-Salvador ◽  
Pablo Rios-Marco ◽  
...  
Keyword(s):  
Antiproliferative Activity ◽  
Kinase Inhibitors ◽  
Human Tumor ◽  
Structure Activity Relationship ◽  
Inhibitory Effect ◽  
Activity Relationship ◽  
Choline Kinase ◽  
Choline Uptake ◽  
Uptake Inhibition ◽  
Structure Activity

Choline kinase inhibitors are an outstanding class of cytotoxic compounds useful for the treatment of different forms of cancer since aberrant choline metabolism is a feature of neoplastic cells. Here, we present the most in-depth structure-activity relationship studies of an interesting series of non-symmetric choline kinase inhibitors previously reported by our group: 3a–h and 4a–h. They are characterized by cationic heads of 3-aminophenol bound to 4-(dimethylamino)- or 4-(pyrrolidin-1-yl)pyridinium through several linkers. These derivatives were evaluated both for their inhibitory activity on the enzyme and their antiproliferative activity in a panel of six human tumor cell lines. The compounds with the N-atom connected to the linker (4a–h) show the best inhibitory results, in the manner of results supported by docking studies. On the contrary, the best antiproliferative compounds were those with the O-atom bounded to the linker (3a–h). On the other hand, as was predictable in both families, the inhibitory effect on the enzyme is better the shorter the length of the linker. However, in tumor cells, lipophilicity and choline uptake inhibition could play a decisive role. Interestingly, compounds 3c and 4f, selected for both their ability to inhibit the enzyme and good antiproliferative activity, are endowed with low toxicity in non-tumoral cells (e.g., human peripheral lymphocytes) concerning cancer cells. These compounds were also able to induce apoptosis in Jurkat leukemic cells without causing significant variations of the cell cycle. It is worth mentioning that these derivatives, besides their inhibitory effect on choline kinase, displayed a modest ability to inhibit choline uptake thus suggesting that this mechanism may also contribute to the observed cytotoxicity.

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