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Journal articles on the topic 'Bitopic'

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Author: Grafiati

Published: 10 December 2022

Last updated: 10 March 2023

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1

Wang, Huiqun, Danni Cao, James C. Gillespie, Rolando E. Mendez, Dana E. Selley, Lee-Yuan Liu-Chen, and Yan Zhang. "Exploring the putative mechanism of allosteric modulations by mixed-action kappa/mu opioid receptor bitopic modulators." Future Medicinal Chemistry 13, no. 6 (March 2021): 551–73. http://dx.doi.org/10.4155/fmc-2020-0308.

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The modulation and selectivity mechanisms of seven mixed-action kappa opioid receptor (KOR)/mu opioid receptor (MOR) bitopic modulators were explored. Molecular modeling results indicated that the ‘message’ moiety of seven bitopic modulators shared the same binding mode with the orthosteric site of the KOR and MOR, whereas the ‘address’ moiety bound with different subdomains of the allosteric site of the KOR and MOR. The ‘address’ moiety of seven bitopic modulators bound to different subdomains of the allosteric site of the KOR and MOR may exhibit distinguishable allosteric modulations to the binding affinity and/or efficacy of the ‘message’ moiety. Moreover, the 3-hydroxy group on the phenolic moiety of the seven bitopic modulators induced selectivity to the KOR over the MOR.

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2

Ferrisi, Rebecca, Beatrice Polini, Caterina Ricardi, Francesca Gado, Kawthar A. Mohamed, Giovanna Baron, Salvatore Faiella, et al. "New Insights into Bitopic Orthosteric/Allosteric Ligands of Cannabinoid Receptor Type 2." International Journal of Molecular Sciences 24, no. 3 (January 21, 2023): 2135. http://dx.doi.org/10.3390/ijms24032135.

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Very recently, we have developed a new generation of ligands targeting the cannabinoid receptor type 2 (CB2R), namely JR compounds, which combine the pharmacophoric portion of the CB2R positive allosteric modulator (PAM), EC21a, with that of the CB2R selective orthosteric agonist LV62, both synthesized in our laboratories. The functional examination enabled us to identify JR14a, JR22a, and JR64a as the most promising compounds of the series. In the current study, we focused on the assessment of the bitopic (dualsteric) nature of these three compounds. Experiments in cAMP assays highlighted that only JR22a behaves as a CB2R bitopic (dualsteric) ligand. In parallel, computational studies helped us to clarify the binding mode of these three compounds at CB2R, confirming the bitopic (dualsteric) nature of JR22a. Finally, the potential of JR22a to prevent neuroinflammation was investigated on a human microglial cell inflammatory model.

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3

Flores-Kim, Josué, and Andrew J. Darwin. "Phage Shock Protein C (PspC) of Yersinia enterocolitica Is a Polytopic Membrane Protein with Implications for Regulation of the Psp Stress Response." Journal of Bacteriology 194, no. 23 (September 28, 2012): 6548–59. http://dx.doi.org/10.1128/jb.01250-12.

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ABSTRACTPhage shock proteins B (PspB) and C (PspC) are integral cytoplasmic membrane proteins involved in inducing theYersinia enterocoliticaPsp stress response. A fundamental aspect of these proteins that has not been studied in depth is their membrane topologies. Variousin silicoanalyses universally predict that PspB is a bitopic membrane protein with the C terminus inside. However, similar analyses yield conflicting predictions for PspC: a bitopic membrane protein with the C terminus inside, a bitopic membrane protein with the C terminus outside, or a polytopic protein with both termini inside. Previous studies ofEscherichia coliPspB-LacZ and PspC-PhoA fusion proteins supported bitopic topologies, with the PspB C terminus inside and the PspC C terminus outside. Here we have used a series of independent approaches to determine the membrane topologies of PspB and PspC inY. enterocolitica. Our data support the predicted arrangement of PspB, with its C terminus in the cytoplasm. In contrast, data from multiple independent approaches revealed that both termini of PspC are located in the cytoplasm. Additional experiments suggested that the C terminus of PspC might be the recognition site for the FtsH protease and an interaction interface with PspA, both of which would be compatible with its newly proposed cytoplasmic location. This unexpected arrangement of PspC allows a new model for events underlying activation of the Psp response, which is an excellent fit with observations from various previous studies.

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4

Gao, Zhan-Guo, Kiran S. Toti, Ryan Campbell, R. Rama Suresh, Huijun Yang, and Kenneth A. Jacobson. "Allosteric Antagonism of the A2A Adenosine Receptor by a Series of Bitopic Ligands." Cells 9, no. 5 (May 12, 2020): 1200. http://dx.doi.org/10.3390/cells9051200.

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Allosteric antagonism by bitopic ligands, as reported for many receptors, is a distinct modulatory mechanism. Although several bitopic A2A adenosine receptor (A2AAR) ligand classes were reported as pharmacological tools, their receptor binding and functional antagonism patterns, i.e., allosteric or competitive, were not well characterized. Therefore, here we systematically characterized A2AAR binding and functional antagonism of two distinct antagonist chemical classes. i.e., fluorescent conjugates of xanthine amine congener (XAC) and SCH442416. Bitopic ligands were potent, weak, competitive or allosteric, based on the combination of pharmacophore, linker and fluorophore. Among antagonists tested, XAC, XAC245, XAC488, SCH442416, MRS7352 showed Ki binding values consistent with KB values from functional antagonism. Interestingly, MRS7396, XAC-X-BY630 (XAC630) and 5-(N,N-hexamethylene)amiloride (HMA) were 9–100 times weaker in displacing fluorescent MRS7416 binding than radioligand binding. XAC245, XAC630, MRS7396, MRS7416 and MRS7322 behaved as allosteric A2AAR antagonists, whereas XAC488 and MRS7395 antagonized competitively. Schild analysis showed antagonism slopes of 0.42 and 0.47 for MRS7396 and XAC630, respectively. Allosteric antagonists HMA and MRS7396 were more potent in displacing [3H]ZM241385 binding than MRS7416 binding. Sodium site D52N mutation increased and decreased affinity of HMA and MRS7396, respectively, suggesting possible preference for different A2AAR conformations. The allosteric binding properties of some bitopic ligands were rationalized and analyzed using the Hall two-state allosteric model. Thus, fluorophore tethering to an orthosteric ligand is not neutral pharmacologically and may confer unexpected properties to the conjugate.

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5

Stank, Lars, Annika Frank, Stefanie Hagenow, and Holger Stark. "Talipexole variations as novel bitopic dopamine D2 and D3 receptor ligands." MedChemComm 10, no. 11 (2019): 1926–29. http://dx.doi.org/10.1039/c9md00379g.

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6

Newitt, John A., Nancy D. Ulbrandt, and Harris D. Bernstein. "The Structure of Multiple Polypeptide Domains Determines the Signal Recognition Particle Targeting Requirement ofEscherichia coli Inner Membrane Proteins." Journal of Bacteriology 181, no. 15 (August 1, 1999): 4561–67. http://dx.doi.org/10.1128/jb.181.15.4561-4567.1999.

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ABSTRACT The signal recognition particle (SRP) targeting pathway is required for the efficient insertion of many polytopic inner membrane proteins (IMPs) into the Escherichia coli inner membrane, but in the absence of SRP protein export proceeds normally. To define the properties of IMPs that impose SRP dependence, we analyzed the targeting requirements of bitopic IMPs that are structurally intermediate between exported proteins and polytopic IMPs. We found that disruption of the SRP pathway inhibited the insertion of only a subset of bitopic IMPs. Studies on a model bitopic AcrB-alkaline phosphatase fusion protein (AcrB 265-AP) showed that the SRP requirement for efficient insertion correlated with the presence of a large periplasmic domain (P1). As previously reported, perturbation of the SRP pathway also affected the insertion of a polytopic AcrB-AP fusion. Even exhaustive SRP depletion, however, failed to block the insertion of any AcrB derivative by more than 50%. Taken together, these data suggest that many proteins that are normally targeted by SRP can utilize alternative targeting pathways and that the structure of both hydrophilic and membrane-spanning domains determines the degree to which the biogenesis of a protein is SRP dependent.

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7

Liu, Jiquan, Yeping Xu, Pedro B. Groszewicz, Martin Brodrecht, Claudia Fasel, Kathrin Hofmann, Xijuan Tan, Torsten Gutmann, and Gerd Buntkowsky. "Novel dirhodium coordination polymers: the impact of side chains on cyclopropanation." Catalysis Science & Technology 8, no. 20 (2018): 5190–200. http://dx.doi.org/10.1039/c8cy01493k.

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8

Adhikari, Pramisha, Bing Xie, Ana Semeano, Alessandro Bonifazi, Francisco O. Battiti, Amy H. Newman, Hideaki Yano, and Lei Shi. "Chirality of Novel Bitopic Agonists Determines Unique Pharmacology at the Dopamine D3 Receptor." Biomolecules 11, no. 4 (April 13, 2021): 570. http://dx.doi.org/10.3390/biom11040570.

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The dopamine D2/D3 receptor (D2R/D3R) agonists are used as therapeutics for Parkinson’s disease (PD) and other motor disorders. Selective targeting of D3R over D2R is attractive because of D3R’s restricted tissue distribution with potentially fewer side-effects and its putative neuroprotective effect. However, the high sequence homology between the D2R and D3R poses a challenge in the development of D3R selective agonists. To address the ligand selectivity, bitopic ligands were designed and synthesized previously based on a potent D3R-preferential agonist PF592,379 as the primary pharmacophore (PP). This PP was attached to various secondary pharmacophores (SPs) using chemically different linkers. Here, we characterize some of these novel bitopic ligands at both D3R and D2R using BRET-based functional assays. The bitopic ligands showed varying differences in potencies and efficacies. In addition, the chirality of the PP was key to conferring improved D3R potency, selectivity, and G protein signaling bias. In particular, compound AB04-88 exhibited significant D3R over D2R selectivity, and G protein bias at D3R. This bias was consistently observed at various time-points ranging from 8 to 46 min. Together, the structure-activity relationships derived from these functional studies reveal unique pharmacology at D3R and support further evaluation of functionally biased D3R agonists for their therapeutic potential.

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9

Potapov, Andrei S., Evgenia A. Nudnova, Vladimir D. Ogorodnikov, Tatiana V. Petrenko, and Andrei I. Khlebnikov. "Synthesis of New Bitopic Tetra(pyrazolyl)-Ligands with Neopentane and O-Xylene Backbones." Scientific World Journal 2012 (2012): 1–5. http://dx.doi.org/10.1100/2012/798271.

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Several new bitopic pyrazole-containing ligands were prepared from the corresponding pyrazoles and tetrahalogen or tetratosyloxy derivatives of o-xylene and neopentane in a superbasic medium (KOH-DMSO).

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10

Schrage, Ramona, and Evi Kostenis. "Functional selectivity and dualsteric/bitopic GPCR targeting." Current Opinion in Pharmacology 32 (February 2017): 85–90. http://dx.doi.org/10.1016/j.coph.2016.12.001.

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11

Cao, Yongkai, Ningning Sun, Jiumei Zhang, Zhiguo Liu, Yi-zhe Tang, Zhengzhi Wu, Kyeong-Man Kim, and Seung Hoon Cheon. "Correction: Design, synthesis, and evaluation of bitopic arylpiperazine-phthalimides as selective dopamine D3 receptor agonists." MedChemComm 9, no. 9 (2018): 1565. http://dx.doi.org/10.1039/c8md90042f.

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Correction for 'Design, synthesis, and evaluation of bitopic arylpiperazine-phthalimides as selective dopamine D₃ receptor agonists' by Yongkai Cao et al., Med. Chem. Commun., 2018, DOI: 10.1039/c8md00237a.

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12

Jakubik, Jan, and Esam E. El-Fakahany. "Current Advances in Allosteric Modulation of Muscarinic Receptors." Biomolecules 10, no. 2 (February 18, 2020): 325. http://dx.doi.org/10.3390/biom10020325.

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Allosteric modulators are ligands that bind to a site on the receptor that is spatially separated from the orthosteric binding site for the endogenous neurotransmitter. Allosteric modulators modulate the binding affinity, potency, and efficacy of orthosteric ligands. Muscarinic acetylcholine receptors are prototypical allosterically-modulated G-protein-coupled receptors. They are a potential therapeutic target for the treatment of psychiatric, neurologic, and internal diseases like schizophrenia, Alzheimer’s disease, Huntington disease, type 2 diabetes, or chronic pulmonary obstruction. Here, we reviewed the progress made during the last decade in our understanding of their mechanisms of binding, allosteric modulation, and in vivo actions in order to understand the translational impact of studying this important class of pharmacological agents. We overviewed newly developed allosteric modulators of muscarinic receptors as well as new spin-off ideas like bitopic ligands combining allosteric and orthosteric moieties and photo-switchable ligands based on bitopic agents.

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13

Valant, C., P. M. Sexton, and A. Christopoulos. "Orthosteric/Allosteric Bitopic Ligands: Going Hybrid at GPCRs." Molecular Interventions 9, no. 3 (June 1, 2009): 125–35. http://dx.doi.org/10.1124/mi.9.3.6.

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14

Niklas, Beata, Bruno Lapied, and Wieslaw Nowak. "In Search of Synergistic Insect Repellents: Modeling of Muscarinic GPCR Interactions with Classical and Bitopic Photoactive Ligands." Molecules 27, no. 10 (May 20, 2022): 3280. http://dx.doi.org/10.3390/molecules27103280.

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Insect vector-borne diseases pose serious health problems, so there is a high demand for efficient molecules that could reduce transmission. Using molecular docking and molecular dynamics (MD) simulation, we studied a series of compounds acting on human and insect muscarinic acetylcholine receptors (mAChRs), a novel target of synergistic agents in pest control. We characterized early conformational changes of human M1 and fruit fly type-A mAChR G protein-coupled receptors (GPCRs) in response to DEET, IR3535, and muscarine binding based on the MD analysis of the activation microswitches known to form the signal transduction pathway in class A GPCRs. We indicated groups of microswitches that are the most affected by the presence of a ligand. Moreover, to increase selectivity towards insects, we proposed a new, bitopic, photoswitchable mAChR ligand—BQCA-azo-IR353 and studied its interactions with both receptors. Modeling data showed that using a bitopic ligand may be a promising strategy in the search for better insect control.

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15

van der Sluis, Eli O., Erhard van der Vries, Greetje Berrelkamp, Nico Nouwen, and Arnold J. M. Driessen. "Topologically Fixed SecG Is Fully Functional." Journal of Bacteriology 188, no. 3 (February 1, 2006): 1188–90. http://dx.doi.org/10.1128/jb.188.3.1188-1190.2006.

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ABSTRACT It has been proposed that the bitopic membrane protein SecG undergoes topology inversion during translocation of (pre)proteins via SecYEG. Here we show that SecG covalently cross-linked to SecY cannot invert its topology while remaining fully functional in protein translocation. Our results strongly disfavor topology inversion of SecG during protein translocation.

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16

Ozgur, Beytullah, Cory D. Dunn, and Mehmet Sayar. "Modeling Adsorption, Conformation, and Orientation of the Fis1 Tail Anchor at the Mitochondrial Outer Membrane." Membranes 12, no. 8 (July 31, 2022): 752. http://dx.doi.org/10.3390/membranes12080752.

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Proteins can be targeted to organellar membranes by using a tail anchor (TA), a stretch of hydrophobic amino acids found at the polypeptide carboxyl-terminus. The Fis1 protein (Fis1p), which promotes mitochondrial and peroxisomal division in the yeast Saccharomyces cerevisiae, is targeted to those organelles by its TA. Substantial evidence suggests that Fis1p insertion into the mitochondrial outer membrane can occur without the need for a translocation machinery. However, recent findings raise the possibility that Fis1p insertion into mitochondria might be promoted by a proteinaceous complex. Here, we have performed atomistic and coarse-grained molecular dynamics simulations to analyze the adsorption, conformation, and orientation of the Fis1(TA). Our results support stable insertion at the mitochondrial outer membrane in a monotopic, rather than a bitopic (transmembrane), configuration. Once inserted in the monotopic orientation, unassisted transition to the bitopic orientation is expected to be blocked by the highly charged nature of the TA carboxyl-terminus and by the Fis1p cytosolic domain. Our results are consistent with a model in which Fis1p does not require a translocation machinery for insertion at mitochondria.

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17

Chen, Joseph C., David S. Weiss, Jean-Marc Ghigo, and Jon Beckwith. "Septal Localization of FtsQ, an Essential Cell Division Protein in Escherichia coli." Journal of Bacteriology 181, no. 2 (January 15, 1999): 521–30. http://dx.doi.org/10.1128/jb.181.2.521-530.1999.

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ABSTRACT Septation in Escherichia coli requires several gene products. One of these, FtsQ, is a simple bitopic membrane protein with a short cytoplasmic N terminus, a membrane-spanning segment, and a periplasmic domain. We have constructed a merodiploid strain that expresses both FtsQ and the fusion protein green fluorescent protein (GFP)-FtsQ from single-copy chromosomal genes. The gfp-ftsQgene complements a null mutation in ftsQ. Fluorescence microscopy revealed that GFP-FtsQ localizes to the division site. Replacing the cytoplasmic and transmembrane domains of FtsQ with alternative membrane anchors did not prevent the localization of the GFP fusion protein, while replacing the periplasmic domain did, suggesting that the periplasmic domain is necessary and sufficient for septal targeting. GFP-FtsQ localization to the septum depended on the cell division proteins FtsZ and FtsA, which are cytoplasmic, but not on FtsL and FtsI, which are bitopic membrane proteins with comparatively large periplasmic domains. In addition, the septal localization of ZipA apparently did not require functional FtsQ. Our results indicate that FtsQ is an intermediate recruit to the division site.

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18

Bocharov, Eduard V., Pavel E. Volynsky, Konstantin V. Pavlov, Roman G. Efremov, and Alexander S. Arseniev. "Structure elucidation of dimeric transmembrane domains of bitopic proteins." Cell Adhesion & Migration 4, no. 2 (April 2010): 284–98. http://dx.doi.org/10.4161/cam.4.2.11930.

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19

Jo, Euijung, Barun Bhhatarai, Emanuela Repetto, Miguel Guerrero, Sean Riley, Steven J. Brown, Yasushi Kohno, Edward Roberts, Stephan C. Schürer, and Hugh Rosen. "Novel Selective Allosteric and Bitopic Ligands for the S1P3Receptor." ACS Chemical Biology 7, no. 12 (September 14, 2012): 1975–83. http://dx.doi.org/10.1021/cb300392z.

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20

Zviling, Moti, Uzi Kochva, and Isaiah T. Arkin. "How important are transmembrane helices of bitopic membrane proteins?" Biochimica et Biophysica Acta (BBA) - Biomembranes 1768, no. 3 (March 2007): 387–92. http://dx.doi.org/10.1016/j.bbamem.2006.11.019.

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21

Lee, Boeun, Michelle Taylor, Suzy A. Griffin, Tamara McInnis, Nathalie Sumien, Robert H. Mach, and Robert R. Luedtke. "Evaluation of Substituted N-Phenylpiperazine Analogs as D3 vs. D2 Dopamine Receptor Subtype Selective Ligands." Molecules 26, no. 11 (May 26, 2021): 3182. http://dx.doi.org/10.3390/molecules26113182.

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N-phenylpiperazine analogs can bind selectively to the D3 versus the D2 dopamine receptor subtype despite the fact that these two D2-like dopamine receptor subtypes exhibit substantial amino acid sequence homology. The binding for a number of these receptor subtype selective compounds was found to be consistent with their ability to bind at the D3 dopamine receptor subtype in a bitopic manner. In this study, a series of the 3-thiophenephenyl and 4-thiazolylphenyl fluoride substituted N-phenylpiperazine analogs were evaluated. Compound 6a was found to bind at the human D3 receptor with nanomolar affinity with substantial D3 vs. D2 binding selectivity (approximately 500-fold). Compound 6a was also tested for activity in two in-vivo assays: (1) a hallucinogenic-dependent head twitch response inhibition assay using DBA/2J mice and (2) an L-dopa-dependent abnormal involuntary movement (AIM) inhibition assay using unilateral 6-hydroxydopamine lesioned (hemiparkinsonian) rats. Compound 6a was found to be active in both assays. This compound could lead to a better understanding of how a bitopic D3 dopamine receptor selective ligand might lead to the development of pharmacotherapeutics for the treatment of levodopa-induced dyskinesia (LID) in patients with Parkinson’s disease.

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22

Boldog, Ishtvan, Joachim Sieler, Alexander N. Chernega, and Konstantin V. Domasevitch. "4,4′-Bipyrazolyl: new bitopic connector for construction of coordination networks." Inorganica Chimica Acta 338 (October 2002): 69–77. http://dx.doi.org/10.1016/s0020-1693(02)00902-7.

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23

Lane, J. Robert, Patrick M. Sexton, and Arthur Christopoulos. "Bridging the gap: bitopic ligands of G-protein-coupled receptors." Trends in Pharmacological Sciences 34, no. 1 (January 2013): 59–66. http://dx.doi.org/10.1016/j.tips.2012.10.003.

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24

Reinecke, Bethany A., Huiqun Wang, and Yan Zhang. "Recent Advances in the Drug Discovery and Development of Dualsteric/ Bitopic Activators of G Protein-Coupled Receptors." Current Topics in Medicinal Chemistry 19, no. 26 (December 10, 2019): 2378–92. http://dx.doi.org/10.2174/1568026619666191009164609.

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G protein-coupled receptors (GPCRs) represent the largest family of proteins targeted by drug design and discovery efforts. Of these efforts, the development of GPCR agonists is highly desirable, due to their therapeutic robust utility in treating diseases caused by deficient receptor signaling. One of the challenges in designing potent and selective GPCR agonists lies in the inability to achieve combined high binding affinity and subtype selectivity, due to the high homology between orthosteric sites among GPCR subtypes. To combat this difficulty, researchers have begun to explore the utility of targeting topographically distinct and less conserved binding sites, namely “allosteric” sites. Pursuing these sites offers the benefit of achieving high subtype selectivity, however, it also can result in a decreased binding affinity and potency as compared to orthosteric agonists. Therefore, bitopic ligands comprised of an orthosteric agonist and an allosteric modulator connected by a spacer and allowing binding with both the orthosteric and allosteric sites within one receptor, have been developed. It may combine the high subtype selectivity of an allosteric modulator with the high binding affinity of an orthosteric agonist and provides desired advantages over orthosteric agonists or allosteric modulators alone. Herein, we review the recent advances in the development of bitopic agonists/activators for various GPCR targets and their novel therapeutic potentials.

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25

Agnihothram, Sudhakar S., Joanne York, Meg Trahey, and Jack H. Nunberg. "Bitopic Membrane Topology of the Stable Signal Peptide in the Tripartite Junín Virus GP-C Envelope Glycoprotein Complex." Journal of Virology 81, no. 8 (January 31, 2007): 4331–37. http://dx.doi.org/10.1128/jvi.02779-06.

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ABSTRACT The stable signal peptide (SSP) of the GP-C envelope glycoprotein of the Junín arenavirus plays a critical role in trafficking of the GP-C complex to the cell surface and in its membrane fusion activity. SSP therefore may function on both sides of the lipid membrane. In this study, we have investigated the membrane topology of SSP by confocal microscopy of cells treated with the detergent digitonin to selectively permeabilize the plasma membrane. By using an affinity tag to mark the termini of SSP in the properly assembled GP-C complex, we find that both the N and C termini reside in the cytosol. Thus, SSP adopts a bitopic topology in which the C terminus is translocated from the lumen of the endoplasmic reticulum to the cytoplasm. This model is supported by (i) the presence of two conserved hydrophobic regions in SSP (hφ1 and hφ2) and (ii) our previous demonstration that lysine-33 in the ectodomain loop is essential for pH-dependent membrane fusion. Moreover, we demonstrate that the introduction of a charged side chain or single amino acid deletion in the membrane-spanning hφ2 region significantly diminishes SSP association in the GP-C complex and abolishes membrane fusion activity. Taken together, our results suggest that bitopic membrane insertion of SSP is centrally important in the assembly and function of the tripartite GP-C complex.

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Cooper, Samantha Louise, Edward Wragg, Julie March, Stephen Hill, and Jeanette Woolard. "Effects of an Adenosine Receptor Bitopic Ligand on The Cardiovascular System." FASEB Journal 34, S1 (April 2020): 1. http://dx.doi.org/10.1096/fasebj.2020.34.s1.02426.

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27

Keov, Peter, Laura López, Shane M. Devine, Celine Valant, J. Robert Lane, Peter J. Scammells, Patrick M. Sexton, and Arthur Christopoulos. "Molecular Mechanisms of Bitopic Ligand Engagement with the M1Muscarinic Acetylcholine Receptor." Journal of Biological Chemistry 289, no. 34 (July 8, 2014): 23817–37. http://dx.doi.org/10.1074/jbc.m114.582874.

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28

Marie, Cécile, Manuel Miguirditchian, Denis Guillaneux, Julia Bisson, Muriel Pipelier, and Didier Dubreuil. "New Bitopic Ligands for the Group Actinide Separation by Solvent Extraction." Solvent Extraction and Ion Exchange 29, no. 2 (March 18, 2011): 292–315. http://dx.doi.org/10.1080/07366299.2011.556923.

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29

Morales, Paula, Gemma Navarro, Marc Gómez‐Autet, Laura Redondo, Javier Fernández‐Ruiz, Laura Pérez‐Benito, Arnau Cordomí, Leonardo Pardo, Rafael Franco, and Nadine Jagerovic. "Discovery of Homobivalent Bitopic Ligands of the Cannabinoid CB 2 Receptor**." Chemistry – A European Journal 26, no. 68 (November 9, 2020): 15839–42. http://dx.doi.org/10.1002/chem.202003389.

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30

Bieller, Susanne, Fan Zhang, Michael Bolte, Jan W. Bats, Hans-Wolfram Lerner, and Matthias Wagner. "Bitopic Bis- and Tris(1-pyrazolyl)borate Ligands: Syntheses and Structural Characterization." Organometallics 23, no. 9 (April 2004): 2107–13. http://dx.doi.org/10.1021/om049954e.

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31

Caldwell, Andreia M., and Ronald L. Smith. "Membrane Topology of the ZntB Efflux System of Salmonella enterica Serovar Typhimurium." Journal of Bacteriology 185, no. 1 (January 1, 2003): 374–76. http://dx.doi.org/10.1128/jb.185.1.374-376.2003.

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ABSTRACT The membrane topology of the ZntB Zn2+ transport protein of Salmonella enterica serovar Typhimurium was determined by constructing deletion derivatives of the protein and genetically fusing them to blaM or lacZ cassettes. The enzymatic activities of the hybrid proteins indicate that ZntB is a bitopic integral membrane protein consisting largely of two independent domains. The first 266 amino acids form a large, highly charged domain within the cytoplasm, while the remaining 61 residues form a small membrane domain containing two membrane-spanning segments. The overall orientation towards the cytoplasm is consistent with the ability of ZntB to facilitate zinc efflux.

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Quadros, Helenita C., Aysun Çapcı, Lars Herrmann, Sarah D’Alessandro, Diana Fontinha, Raquel Azevedo, Wilmer Villarreal, et al. "Studies of Potency and Efficacy of an Optimized Artemisinin-Quinoline Hybrid against Multiple Stages of the Plasmodium Life Cycle." Pharmaceuticals 14, no. 11 (November 6, 2021): 1129. http://dx.doi.org/10.3390/ph14111129.

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A recently developed artemisinin-quinoline hybrid, named 163A, has been shown to display potent activity against the asexual blood stage of Plasmodium, the malaria parasite. In this study, we determined its in vitro cytotoxicity to mammalian cells, its potency to suppress P. berghei hepatic infection and to decrease the viability of P. falciparum gametocytes, in addition to determining whether the drug exhibits efficacy of a P. berghei infection in mice. This hybrid compound has a low level of cytotoxicity to mammalian cells and, conversely, a high level of selectivity. It is potent in the prevention of hepatic stage development as well as in killing gametocytes, denoting a potential blockage of malaria transmission. The hybrid presents a potent inhibitory activity for beta-hematin crystal formation, in which subsequent assays revealed that its endoperoxide component undergoes bioactivation by reductive reaction with ferrous heme towards the formation of heme-drug adducts; in parallel, the 7-chloroquinoline component has binding affinity for ferric hemin. Both structural components of the hybrid co-operate to enhance the inhibition of beta-hematin, and this bitopic ligand property is essential for arresting the growth of asexual blood parasites. We demonstrated the in vivo efficacy of the hybrid as an erythrocytic schizonticide agent in comparison to a chloroquine/artemisinin combination therapy. Collectively, the findings suggest that the bitopic property of the hybrid is highly operative on heme detoxification suppression, and this provides compelling evidence for explaining the action of the hybrid on the asexual blood stage. For sporozoite and gametocyte stages, the hybrid conserves the potency typically observed for endoperoxide drugs, and this is possibly achieved due to the redox chemistry of endoperoxide components with ferrous heme.

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Foster, Scott, Andrew Lee, Cristina Maranto, Joshua E. Allen, Randall Lanier, Phiroze Sethna, and Varun V. Prabhu. "EXTH-104. ROLE OF CLPP AND MITOCHONDRIAL METABOLISM IN THE ANTI-CANCER EFFECTS OF IMIPRIDONE ONC201 AND ONC206 IN GLIOBLASTOMA AND DIPG." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii234. http://dx.doi.org/10.1093/neuonc/noac209.902.

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Abstract ONC201 is the first bitopic dopamine receptor D2 (DRD2) antagonist and allosteric mitochondrial protease ClpP agonist. ONC201 is well tolerated and induces durable tumor regressions in H3 K27M-mutant glioma patients. ONC206, a derivative of ONC201 currently in Phase I trials, is also a bitopic DRD2 antagonist and ClpP agonist with enhanced nanomolar potency relative to ONC201. We evaluated in vitro efficacy, mechanism(s) of action and acquired resistance for ONC201 and ONC206 in glioblastoma (GBM) (T98G, A172, U87MG), H3.3 K27M mutant DIPG (SF8628, SF7761) and astrocytoma (H4, U118MG) cell lines. ONC206 was more potent than ONC201 in cell viability assays for all line. A mutation in ClpP has previously been associated with resistance to imipridones. Accordingly, SF8628 cells with a CRISPR-mediated ClpP knockout were resistant to both ONC201 and ONC206. Polyclonal resistant cell lines were generated through prolonged passaging in increasing concentrations of ONC201 (SF8628 and T98G cells) or ONC206 (T98G cells). Cells with acquired resistance to ONC201 (ONC201Res) or ONC206 (ONC206Res) showed cross resistance to both imipridones. Time-stability of resistance was confirmed by removing drug for 2 to 4 weeks and retesting. Whole genome sequencing revealed ClpP mutations in both ONC201Res and ONC206Res T98G cells. RNAseq analysis revealed upregulation of the integrated stress response, apoptosis pathways, and amino acid metabolism with imipridone treatment in T98G parental cells but not resistant clones. Depleting glucose in the media enhanced cell viability inhibition by imipridones, indicating mitochondrial metabolism may contribute to their mechanism of action. Our results identify ClpP and mitochondrial metabolism as key aspects for the mechanism of action of ONC201 and ON206 in DIPG and GBM cell lines.

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Perez, Daniel, Ana Martinez, Carmen Gil, and Nuria Campillo. "From Bitopic Inhibitors to Multitarget Drugs for the Future Treatment of Alzheimer’s Disease." Current Medicinal Chemistry 22, no. 33 (November 13, 2015): 3789–806. http://dx.doi.org/10.2174/0929867322666150812145825.

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35

Holzgrabe, Ulrike, and Michael Decker. "Bitopic muscarinic agonists and antagonists and uses thereof: a patent evaluation of US20160136145A1." Expert Opinion on Therapeutic Patents 27, no. 2 (December 26, 2016): 121–25. http://dx.doi.org/10.1080/13543776.2017.1272577.

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36

Lomize, Andrei L., Jacob M. Hage, and Irina D. Pogozheva. "Membranome 2.0: database for proteome-wide profiling of bitopic proteins and their dimers." Bioinformatics 34, no. 6 (November 6, 2017): 1061–62. http://dx.doi.org/10.1093/bioinformatics/btx720.

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37

Tahtaoui, Chouaib, Isabelle Parrot, Philippe Klotz, Fabrice Guillier, Jean-Luc Galzi, Marcel Hibert, and Brigitte Ilien. "Fluorescent Pirenzepine Derivatives as Potential Bitopic Ligands of the Human M1 Muscarinic Receptor." Journal of Medicinal Chemistry 47, no. 17 (August 2004): 4300–4315. http://dx.doi.org/10.1021/jm040800a.

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Volpato, Daniela, Michael Kauk, Regina Messerer, Marcel Bermudez, Gerhard Wolber, Andreas Bock, Carsten Hoffmann, and Ulrike Holzgrabe. "The Role of Orthosteric Building Blocks of Bitopic Ligands for Muscarinic M1 Receptors." ACS Omega 5, no. 49 (December 1, 2020): 31706–15. http://dx.doi.org/10.1021/acsomega.0c04220.

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39

Reger, Daniel L., Russell P. Watson, and Mark D. Smith. "An Organoplatinum(II) Complex of a Bitopic, Propylene-linked Bis(pyrazolyl)methane Ligand." Journal of Chemical Crystallography 38, no. 1 (October 24, 2007): 17–20. http://dx.doi.org/10.1007/s10870-007-9264-z.

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40

Bocharov, Eduard V., Dmitry M. Lesovoy, Olga V. Bocharova, Anatoly S. Urban, Yaroslav V. Bershacky, Pavel E. Volynsky, Roman G. Efremov, and Alexander S. Arseniev. "The Role of Protein-Lipid Interactions in the Functioning of Bitopic Membrane Proteins." Biophysical Journal 118, no. 3 (February 2020): 211a. http://dx.doi.org/10.1016/j.bpj.2019.11.1259.

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41

Reger, Daniel L., Andrea E. Pascui, and Mark D. Smith. "Structural Variations in Copper(II) Complexes of a Bitopic Bis(pyrazolyl)methane Ligand." European Journal of Inorganic Chemistry 2012, no. 29 (May 25, 2012): 4593–604. http://dx.doi.org/10.1002/ejic.201200118.

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42

Meijer, Femke A., Guido J. M. Oerlemans, and Luc Brunsveld. "Orthosteric and Allosteric Dual Targeting of the Nuclear Receptor RORγt with a Bitopic Ligand." ACS Chemical Biology 16, no. 3 (February 17, 2021): 510–19. http://dx.doi.org/10.1021/acschembio.0c00941.

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43

Valant, Celine, J. Robert Lane, Patrick M. Sexton, and Arthur Christopoulos. "The Best of Both Worlds? Bitopic Orthosteric/Allosteric Ligands of G Protein–Coupled Receptors." Annual Review of Pharmacology and Toxicology 52, no. 1 (February 10, 2012): 153–78. http://dx.doi.org/10.1146/annurev-pharmtox-010611-134514.

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Chiu, Pei Ling, Chih Yuan Chen, Chun-Chin Lee, Meng-Hua Hsieh, Chuan-Hung Chuang, and Hon Man Lee. "Structural Variations in Novel Silver(I) Complexes with Bitopic Pyrazole/N-Heterocyclic Carbene Ligands." Inorganic Chemistry 45, no. 6 (March 2006): 2520–30. http://dx.doi.org/10.1021/ic051840n.

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Cao, Yongkai, Ningning Sun, Jiumei Zhang, Zhiguo Liu, Yi-zhe Tang, Zhengzhi Wu, Kyeong-Man Kim, and Seung Hoon Cheon. "Design, synthesis, and evaluation of bitopic arylpiperazine-phthalimides as selective dopamine D3 receptor agonists." MedChemComm 9, no. 9 (2018): 1457–65. http://dx.doi.org/10.1039/c8md00237a.

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Cao, Han, Marcus C. K. Ng, Siti Azma Jusoh, Hio Kuan Tai, and Shirley W. I. Siu. "TMDIM: an improved algorithm for the structure prediction of transmembrane domains of bitopic dimers." Journal of Computer-Aided Molecular Design 31, no. 9 (September 2017): 855–65. http://dx.doi.org/10.1007/s10822-017-0047-0.

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47

Lider, Sukhikh, Smolentsev, Semitut, Filatov, and Potapov. "Synthesis, Crystal Structure, Thermal Analysis, and DFT Calculations of Molecular Copper(II) Chloride Complexes with Bitopic Ligand 1,1,2,2-tetrakis(pyrazol-1-yl)ethane." Crystals 9, no. 4 (April 24, 2019): 222. http://dx.doi.org/10.3390/cryst9040222.

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Two binuclear coordination compounds of Cu(II) chloride with the bitopic ligand 1,1,2,2-tetrakis(pyrazol-1-yl)ethane (Pz4) of the composition [Cu2(µ2Pz4)(DMSO)2Cl4]·4H2O and [Cu2(µ2Pz4)(DMSO)2Cl4]∙2DMSO were prepared and characterized by elemental analysis, IR spectroscopy, thermogravimetric analysis, single-crystal X-ray diffraction, and powder diffraction analysis. It was shown that in contrast to silver(I) and copper(II) nitrates, copper(II) chloride forms discrete complexes instead of coordination polymers. The supramolecular structure of the complex [Cu2(µ2Pz4)(DMSO)2Cl4]·4H2O with lattice water molecules is formed by OH···Cl and OH···O hydrogen bonds. Density functional theory (DFT) calculations of vibrational frequencies of the ligand and its copper(II) complex allowed for assigning IR bands to specific vibrations.

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Prabhu, Varun, Caroline Cuoco, Jinkyu Jung, Abed Rahman Kawakibi, Blair Willette, Marilyn Day, Lakshmi Anantharaman, et al. "DDIS-20. IMIPRIDONE STRUCTURE ACTIVITY RELATIONSHIP UNCOVERS ONC206 AS THE NEXT BITOPIC DRD2 ANTAGONIST FOR ONCOLOGY WITH DIFFERENTIATED RECEPTOR PHARMACOLOGY." Neuro-Oncology 21, Supplement_6 (November 2019): vi67. http://dx.doi.org/10.1093/neuonc/noz175.271.

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Abstract ONC201 is the first bitopic antagonist of dopamine receptor D2 (DRD2) in oncology clinical trials, which have shown that the small molecule is well tolerated and induces durable tumor regressions in H3 K27M-mutant glioma patients. ONC201 possesses a unique tri-heterocyclic core structure that prompted a medicinal chemistry exploration following its successful clinical translation. Chemical derivatization of the ONC201 pharmacophore from an angular to a linear isomer ablated DRD2 antagonist activity and anti-cancer activity, indicating the core structure integrity is critical. A series of analogs that share the same core structure, called imipridones, were profiled for modulation of β-arrestin recruitment to GPCRs and anti-cancer efficacy. The profiled imipridones exhibited a heterogeneous spectrum of GPCR agonist/antagonist activity that was exclusive to Class A GPCRs. The addition of electron withdrawing groups to one of two peripheral benzyl rings enhanced the potency of GPCR engagement and anti-cancer effects, while derivatization of the other benzyl ring was inactivating. Among the GPCR hits identified, maximal variance in imipridone GPCR antagonism was identified for DRD2/DRD3. ONC206 emerged as the most selective and potent antagonist for DRD2/DRD3 with a Ki of ~320nM for DRD2 with complete specificity across human GPCRs and complete DRD2 antagonism. Schild analyses of ONC206 in cAMP and β-Arrestin recruitment assays revealed hallmarks of non-competitive DRD2 antagonism, unlike antipsychotics but similar to ONC201. Shotgun mutagenesis across DRD2 identified 7 residues critical for ONC206-mediated antagonism at orthosteric and allosteric sites. Six residues were critical for ONC201 and ONC206, however the impact varied between the two compounds and one allosteric residue was exclusive to ONC206. Structural mapping revealed that some ONC206-critical allosteric residue interactions are located at the interface of TM-IV and –V that mediates the DRD2 homodimer interface. Thus, ONC206 is a bitopic DRD2 antagonist that may be poised to address oncogenic DRD2 monomers or dimers.

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Prabhu, Varun, Abed Rahman Kawakibi, Neel Madhukar, Mathew Garnett, Ultan McDermott, Cyril Benes, Robert Wechsler-Reya, et al. "EXTH-71. IND-ENABLING CHARACTERIZATION OF ONC206 AS THE NEXT BITOPIC DRD2 ANTAGONIST FOR NEURO-ONCOLOGY." Neuro-Oncology 21, Supplement_6 (November 2019): vi97. http://dx.doi.org/10.1093/neuonc/noz175.401.

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Abstract ONC201 is the first clinical bitopic antagonist of DRD2, an oncogenic receptor in brain and neuroendocrine tumors. ONC206, a derivative of ONC201 that shares the imipridone core structure, is also a bitopic DRD2 antagonist that exhibits enhanced non-competitive effects, high specificity, nanomolar potency, and disruption of DRD2 homodimers. Broad nanomolar efficacy of ONC206 (GI50 < 78-889nM, CellTitre-Glo, 72h) was observed in >1,000 GDSC cancer cell lines. Maximal ONC206 sensitivity was observed in pheochromocytoma, high-grade gliomas, neuroblastoma, medulloblastoma, sarcoma and cholangiocarcinoma cell lines exhibiting a DRD2+/DRD5- RNA expression signature. An exposure time of 48h at nanomolar concentrations was sufficient for maximal inhibition of tumor cell viability. ONC206 reduced the viability of normal human fibroblasts at higher doses (GI50 > 5µM), suggesting a wide therapeutic window. Antitumor efficacy without body weight loss was observed with 50 mg/kg weekly oral ONC206 in a dopamine-secreting HuCCT1 cholangiocarcinoma subcutaneous xenograft model. Biodistribution studies in Sprague-Dawley rats revealed a ~12 µM plasma Cmax with a systemic terminal half-life of ~6 hours upon a single oral dose of 50 mg/kg. Additionally, 5–10 fold higher ONC206 concentrations were observed in adrenal gland, bile duct, brain and bone marrow relative to plasma. Nanomolar concentrations were also observed in the CSF above DRD2 antagonism thresholds, unlike ONC201. GLP toxicology studies with weekly oral ONC206 in Sprague-Dawley rats and beagle dogs revealed no dose-limiting toxicities. Mild and reversible decreased body weight and/or body weight gain with no effects on food consumption were observed at the highest evaluated dose in both species. The highest non-severely toxic dose (HNSTD) was ≥ 16.7 mg/kg in dogs and ≥ 50 mg/kg in rats that exceeds efficacious doses in preclinical models. Using standard allometric scaling, a 90 mg starting dose of ONC206 was selected for the first-in-human clinical trial in biomarker-defined adult recurrent CNS tumors.

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Prabhu, Varun, Sara Morrow, Abed Rahman Kawakibi, Yulia Jitkova, Jinkyu Jung, Neel Madhukar, Mathew Garnett, et al. "EXTH-74. IND-ENABLING CHARACTERIZATION OF DUAL DRD2- AND ClpP-TARGETING AGENT ONC206 AS THE NEXT IMIPRIDONE FOR CLINICAL NEURO-ONCOLOGY." Neuro-Oncology 22, Supplement_2 (November 2020): ii103. http://dx.doi.org/10.1093/neuonc/noaa215.428.

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Abstract ONC201 is the first bitopic antagonist of dopamine receptor D2 (DRD2) and allosteric mitochondrial protease ClpP agonist, that is well tolerated and induces durable tumor regressions in H3 K27M-mutant glioma patients. ONC206, a derivative of ONC201, is also a bitopic DRD2 antagonist that exhibits enhanced non-competitive effects, nanomolar potency, and disruption of DRD2 homodimers. In these studies, a FITC-casein degradation assay revealed that ONC206 also acts as an agonist of human ClpP and has a 3-fold improved potency. GEPIA database analysis showed ClpP mRNA was overexpressed in glioblastoma cells relative to normal cells. Broad nanomolar efficacy of ONC206 (GI50 < 78-889nM, 72h) was observed in >1,000 GDSC cancer cell lines with the highest sensitivity in cell lines exhibiting high ClpP and/or DRD2+/DRD5- RNA expression signatures. Among solid tumors, nervous system related cell lines were particularly sensitive. ONC206 reduced the viability of normal human fibroblasts at higher doses (GI50 > 5µM), suggesting a wide therapeutic window. Antitumor efficacy without body weight loss was observed with 50 mg/kg weekly oral ONC206 in a subcutaneous xenograft model of DRD2-overexpressing, dopamine-secreting tumor cells. Oral ONC206 at 50mg/kg exhibited a ~12 µM plasma Cmax and ~6 hours terminal half-life in Sprague-Dawley rats. Additionally, 5–10 fold higher ONC206 concentrations were observed in adrenal gland, bile duct, brain and bone marrow relative to plasma. GLP toxicology studies with weekly oral ONC206 in Sprague-Dawley rats and beagle dogs revealed no dose-limiting toxicities. Mild and reversible body weight changes were observed at the highest evaluated dose in both species. The no-observed-adverse-effect level was ≥ 16.7 mg/kg in dogs and ≥ 50 mg/kg in rats that exceed efficacious doses. A 50 mg starting dose of ONC206 was selected for the first-in-human open label, dose escalation, and food effect Phase I study in biomarker-enriched adult recurrent primary CNS tumors.

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