Syntheses and anti-HIV and human cluster of differentiation 4 (CD4) down-modulating potencies of pyridine-fused cyclotriazadisulfonamide (CADA) compounds

Lumangtad, Liezel A.; Claeys, Elisa; Hamal, Sunil; Intasiri, Amarawan; Basrai, Courtney; Yen‐Pon, Expédite; Beenfeldt, Davison; Vermeire, Kurt; Bell, Thomas W.

doi:10.1016/j.bmc.2020.115816

Cited by 8 publications

(5 citation statements)

References 108 publications

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“…Hence, via the study of individual proteins [6,97,104] together with a global proteomics-based approach [103], it was the resistance of type III and type III-like TMPs to such compounds which revealed a previously unanticipated level of complexity that was incompatible with the prevailing models of TMP biogenesis [7,8,83]. Given that many of the TMP clients of the Sec61 complex are drug targets [133], Sec61 inhibitors are promising candidates for therapeutic development; particularly since they appear well tolerated in vivo [134][135][136][137] and have demonstrated promising analgesic [134], antibacterial [138], anti-inflammatory [135], antitumour [136] and antiviral [139][140][141] activity.…”

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confidence: 99%

Membrane protein biogenesis at the ER: the highways and byways

2021

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The Sec61 complex is the major protein translocation channel of the endoplasmic reticulum (ER), where it plays a central role in the biogenesis of membrane and secretory proteins. Whilst Sec61-mediated protein translocation is typically coupled to polypeptide synthesis, suggestive of significant complexity, an obvious characteristic of this core translocation machinery is its surprising simplicity. Over thirty years after its initial discovery, we now understand that the Sec61 complex is in fact the central piece of an elaborate jigsaw puzzle, which can be partly solved using new research findings. We propose that the Sec61 complex acts as a dynamic hub for cotranslational protein translocation at the ER, proactively recruiting a range of accessory complexes that enhance and regulate its function in response to different protein clients. It is now clear that the Sec61 complex does not have a monopoly on co-translational insertion, with some transmembrane proteins preferentially utilising the ER membrane complex instead. We also have a better understanding of post-insertion events, where at least one membrane-embedded chaperone complex can capture the newly inserted transmembrane domains of multi-span proteins and co-ordinate their assembly into a native structure. Having discovered this array of Sec61-associated components and competitors, our next challenge is to understand how they act together in order to expand the range and complexity of the membrane proteins that can be synthesised at the ER. Furthermore, this diversity of components and pathways may open up new opportunities for targeted therapeutic interventions designed to selectively modulate protein biogenesis at the ER. AbbreviationsBiP, immunoglobulin binding protein; CCDC47, coiled-coil domain containing 47 protein, also known as calumin; EMC, ER membrane complex; ER, endoplasmic reticulum; GET, guided entry of tail-anchored proteins; hSnd2, human SRP-independent protein 2, also known as TMEM208; NAC, nascent polypeptide-associated complex; NOMO, nodal modulating protein; PAT, protein associated with the ER translocon; RNC, ribosome-nascent chain; SGTA, small glutamine-rich tetratricopeptide repeat-containing protein alpha; SND, SRPindependent proteins or pathway; SPC, signal peptidase complex; SRP, signal recognition particle; TA, tail-anchored; TMCO1, transmembrane and coiled-coil domains 1 protein; TMD, transmembrane domain; TMEM147, transmembrane protein 147; TMEM208, transmembrane protein 208; TMP, transmembrane protein; TRAM, translocating chain-associated membrane protein; TRAP, transloconassociated protein; TRC40, transmembrane recognition complex of 40 kDa, also known as Asna1.

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confidence: 99%

Membrane protein biogenesis at the ER: the highways and byways

2021

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“…The syntheses of 1 , 3 , and 7 (Figure ) have been reported previously. − Compounds 2 , 4 , 5 , and 6 (Figure ) are new, and details of their synthesis and characterization appear in the experimental section of this publication. Previously reported intermediates , were used to prepare both 2 and 4 in one synthetic step.…”

Section: Resultsmentioning

confidence: 77%

Reduction of Progranulin-Induced Breast Cancer Stem Cell Propagation by Sortilin-Targeting Cyclotriazadisulfonamide (CADA) Compounds

et al. 2021

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Cyclotriazadisulfonamide (CADA) compounds selectively down-modulate two human proteins of potential therapeutic interest, cluster of differentiation 4 (CD4) and sortilin. Progranulin is secreted from some breast cancer cells, causing dedifferentiation of receiving cancer cells and cancer stem cell proliferation. Inhibition of progranulin binding to sortilin, its main receptor, can block progranulin-induced metastatic breast cancer using a triple-negative in vivo xenograft model. In the current study, seven CADA compounds (CADA, VGD020, VGD071, TL020, TL023, LAL014, and DJ010) were examined for reduction of cellular sortilin expression and progranulin-induced breast cancer stem cell propagation. In addition, inhibition of progranulin-induced mammosphere formation was examined and found to be most significant for TL020, TL023, VGD071, and LAL014. Full experimental details are given for the synthesis and characterization of the four new compounds (TL020, TL023, VGD071, and DJ010). Comparison of solubilities, potencies, and cytotoxicities identified VGD071 as a promising candidate for future studies using mouse breast cancer models.

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“…The relatively small size of CADA stimulated the synthesis of numerous analogs that could be implemented in SAR studies [ 102 , 163 , 164 , 165 , 166 , 167 , 168 , 169 ]. These SAR studies were all based on the biological effect of CADA analogs on the cellular expression of the huCD4 receptor, and structure optimization resulted in improved activity going from µM to the nM range [ 165 ].…”

Section: Translocation Inhibitors Of the Sec61 Dependent Protein Translocation Pathwaymentioning

confidence: 99%

Inhibitors of the Sec61 Complex and Novel High Throughput Screening Strategies to Target the Protein Translocation Pathway

Pauwels

Schülein

Vermeire

2021

IJMS

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Proteins targeted to the secretory pathway start their intracellular journey by being transported across biological membranes such as the endoplasmic reticulum (ER). A central component in this protein translocation process across the ER is the Sec61 translocon complex, which is only intracellularly expressed and does not have any enzymatic activity. In addition, Sec61 translocon complexes are difficult to purify and to reconstitute. Screening for small molecule inhibitors impairing its function has thus been notoriously difficult. However, such translocation inhibitors may not only be valuable tools for cell biology, but may also represent novel anticancer drugs, given that cancer cells heavily depend on efficient protein translocation into the ER to support their fast growth. In this review, different inhibitors of protein translocation will be discussed, and their specific mode of action will be compared. In addition, recently published screening strategies for small molecule inhibitors targeting the whole SRP-Sec61 targeting/translocation pathway will be summarized. Of note, slightly modified assays may be used in the future to screen for substances affecting SecYEG, the bacterial ortholog of the Sec61 complex, in order to identify novel antibiotic drugs.

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Syntheses and anti-HIV and human cluster of differentiation 4 (CD4) down-modulating potencies of pyridine-fused cyclotriazadisulfonamide (CADA) compounds

Cited by 8 publications

References 108 publications

Membrane protein biogenesis at the ER: the highways and byways

Membrane protein biogenesis at the ER: the highways and byways

Reduction of Progranulin-Induced Breast Cancer Stem Cell Propagation by Sortilin-Targeting Cyclotriazadisulfonamide (CADA) Compounds

Inhibitors of the Sec61 Complex and Novel High Throughput Screening Strategies to Target the Protein Translocation Pathway

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