| 1. |
- Collins, Patrick M., et al.
(författare)
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Taloside Inhibitors of Galectin-1 and Galectin-3
- 2012
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Ingår i: Chemical Biology and Drug Design. - : Wiley. - 1747-0285 .- 1747-0277. ; 79:3, s. 339-346
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Tidskriftsartikel (refereegranskat)abstract
- Galectin-1 and galectin-3 have roles in cancer and inflammation. Galectin-1 has recently emerged as a significant protein produced by tumour cells to promote tumour development, angiogenesis and metastasis and consequently represents an important target to inhibit. The design of inhibitors targeting the carbohydrate recognition domain that is known to recognize galactose is an important approach in the fight against cancer. Based on the analysis of crystal structures, we pursued the concept that if the galactose was replaced with talose (the C2 epimer of galactose) as a scaffold, then O2 substituents would be directed closer to the protein surface and provide opportunity to design inhibitors that are more specific towards particular galectins. Our elucidation of X-ray crystal structures of two of our synthesized talosides in complex with galectin-1 and galectin-3 provides the first atomic information on the interactions of galectins, and indeed any protein, with talosides. These results have enabled a structure-based rationale for the specificity differences shown by galectin-1 and galectin-3 towards these talosides and demonstrate new opportunities for further exploitation as specific inhibitors of galectins.
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| 2. |
- Rogers, Kathleen E., et al.
(författare)
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Novel Cruzain Inhibitors for the Treatment of Chagas' Disease
- 2012
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Ingår i: Chemical Biology and Drug Design. - : Wiley. - 1747-0277 .- 1747-0285. ; 80:3, s. 398-405
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Tidskriftsartikel (refereegranskat)abstract
- The protozoan parasite Trypanosoma cruzi, the etiological agent of Chagas disease, affects millions of individuals and continues to be an important global health concern. The poor efficacy and unfavorable side effects of current treatments necessitate novel therapeutics. Cruzain, the major cysteine protease of T.similar to cruzi, is one potential novel target. Recent advances in a class of vinyl sulfone inhibitors are encouraging; however, as most potential therapeutics fail in clinical trials and both disease progression and resistance call for combination therapy with several drugs, the identification of additional classes of inhibitory molecules is essential. Using an exhaustive virtual-screening and experimental validation approach, we identify several additional small-molecule cruzain inhibitors. Further optimization of these chemical scaffolds could lead to the development of novel drugs useful in the treatment of Chagas disease.
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| 3. |
- Albericio, Fernando, et al.
(författare)
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Trishomocubane amino acid as a β-turn scaffold
- 2008
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Ingår i: Chemical biology & drug design. - : Wiley. - 1747-0277 .- 1747-0285. ; 71:2, s. 125-130
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Tidskriftsartikel (refereegranskat)abstract
- The synthesis and X-ray structure of two diasteriomeric heptapeptides [Ac-Ala-Ala-Ala-(R/S)-Cage-Ala-Ala-Ala-NH2] with a trishomocubane amino acid as a beta-turn scaffold are reported. The amino acid was synthesized as a racemate and two diastereomeric peptides were obtained. The two peptides were separated by preparative high-pressure liquid chromatography and crystals suitable for X-ray analysis were grown for both diasteriomeric peptides. In general, both the peptides satisfy the criteria for beta-turn conformations. Five of the six Ala residues of both cage peptide crystals satisfy the criteria for 3(10)-helix characteristics and the cage amino acid residue satisfied the m-helix classification. These experimental results confirm previous theoretical studies in our laboratory which predicted that the cage moiety would be a strong/active beta-turn inducer.
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| 4. |
- Bergström, Maria, et al.
(författare)
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Cholera toxin inhibitors studied with High-performance liquid affinity chromatography: arobust method to evaluate receptor-ligand interactions
- 2009
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Ingår i: Chemical Biology and Drug Design. - : Wiley. - 1747-0277 .- 1747-0285. ; 73:1, s. 132-141
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Tidskriftsartikel (refereegranskat)abstract
- Anti-adhesion drugs may be an alternative to antibiotics to control infection of micro-organisms. The well-characterized interaction between cholera toxin and the cellular glycolipid GM1 makes it an attractive model for inhibition studies in general. In this report, we demonstrate a high-performance liquid affinity chromatography approach called weak affinity chromatography to evaluate cholera toxin inhibitors. The cholera toxin B-subunit was covalently coupled to porous silica and a (weak) affinity column was produced. The K(D) values of galactose and meta-nitrophenyl alpha-d-galactoside were determined with weak affinity chromatography to be 52 and 1 mm, respectively, which agree well with IC(50) values previously reported. To increase inhibition potency multivalent inhibitors have been developed and the interaction with multivalent glycopolypeptides was also evaluated. The affinity of these compounds was found to correlate with the galactoside content but K(D) values were not obtained because of the inhomogeneous response and slow off-rate from multivalent interactions. Despite the limitations in obtaining direct K(D) values of the multivalent galactopolypeptides, weak affinity chromatography represents an additional and valuable tool in the evaluation of monovalent as well as multivalent cholera toxin inhibitors. It offers multiple advantages, such as a low sample consumption, high reproducibility and short analysis time, which are often not observed in other methods of analysis.
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| 5. |
- Fayad, Walid, et al.
(författare)
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Identification of Agents that Induce Apoptosis of Multicellular Tumour Spheroids : Enrichment for Mitotic Inhibitors with Hydrophobic Properties
- 2011
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Ingår i: Chemical Biology and Drug Design. - : Wiley. - 1747-0277 .- 1747-0285. ; 78:4, s. 547-557
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Tidskriftsartikel (refereegranskat)abstract
- Cell-based anticancer drug screening generally utilizes rapidly proliferating tumour cells grown as monolayer cultures. Hit compounds from such screens are not necessarily effective on hypoxic and slowly proliferating cells in 3-D tumour tissue. The aim of this study was to examine the potential usefulness of 3-D cultured tumour cells for anticancer drug screening. We used colon carcinoma multicellular spheroids containing hypoxic and quiescent cells in core areas for this purpose. Three libraries (similar to 11 000 compounds) were screened using antiproliferative activity and/or apoptosis as end-points. Screening of monolayer and spheroid cultures was found to identify different sets of hit compounds. Spheroid screening enriched for hydrophobic compounds: median XLogP values of 4.3 and 4.4 were observed for the hits in two independent screening campaigns. Mechanistic analysis revealed that the majority of spheroid screening hits were microtubuli inhibitors. One of these inhibitors was examined in detail and found to be effective against non-dividing cells in the hypoxic centres of spheroids. Spheroid screening represents a conceptually new strategy for anticancer drug discovery. Our findings have implications for drug library design and hit selection in projects aimed to develop drugs for the treatment of solid tumours.
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| 6. |
- Gach, Katarzyna, et al.
(författare)
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The influence of opioids on urokinase plasminogen activator on protein and mRNA level in MCF-7 breast cancer cell line.
- 2009
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Ingår i: Chemical biology & drug design. - : Wiley. - 1747-0285 .- 1747-0277. ; 74:4, s. 390-6
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Tidskriftsartikel (refereegranskat)abstract
- Urokinase plasminogen activator plays a key role in tumor-associated processes, increasing cancer cell invasion and metastasis, and is therefore used as a marker in cancer prognosis. In this study, we have determined the effect of mu-opioid receptor agonists and antagonists on the urokinase plasminogen activator secretion in MCF-7 cell line. It was shown that mu-opioid receptor agonists, such as morphine and endomorphins, greatly stimulate urokinase plasminogen activator secretion, while naloxone and MOR-selective antagonists elicit the opposite effect. The same tendency was observed also on the urokinase plasminogen activator mRNA level. However, neither agonists nor antagonists had any effect on proliferation of MCF-7 cells. The findings reported in this study may be useful in designing further experiments aimed at elucidating the role of the opioid system in cancer cells.
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| 7. |
- Hossain, M. Akhter, et al.
(författare)
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The structural and functional role of the B-chain C-terminal arginine in the relaxin-3 peptide antagonist, R3(B Delta 23-27)R/I5.
- 2009
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Ingår i: Chemical Biology and Drug Design. - : Wiley. - 1747-0277 .- 1747-0285. ; 73:1, s. 46-52
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Tidskriftsartikel (refereegranskat)abstract
- Relaxin-3, a member of the insulin superfamily, is involved in regulating stress and feeding behavior. It is highly expressed in the brain and is the endogenous ligand for the receptor RXFP3. As relaxin-3 also interacts with the relaxin receptor RXFP1, selective agonists and antagonists are crucial for studying the physiological function(s) of the relaxin-3/RXFP3 pair. The analog R3(B Delta 23-27)R/I5, in which a C-terminally truncated human relaxin-3 (H3) B-chain is combined with the INSL5 A-chain, is a potent selective RXFP3 antagonist and has an Arg residue remaining on the B-chain C-terminus as a consequence of the recombinant protein production process. To investigate the role of this residue in the RXFP3 receptor binding and activation, the analogs R3(B Delta 23-27)R/I5 and R3(B Delta 23-27)R containing the B-chain C-terminal Arg as well as R3(B Delta 23-27)/I5 and R3(B Delta 23-27), both lacking the Arg, were chemically assembled and their secondary structure and receptor activity assessed. The peptides generally had a similar conformation but those with the extra Arg residue displayed a significantly increased affinity for the RXFP3. Interestingly, in contrast to R3(B Delta 23-27)R and R3(B Delta 23-27)R/I5, the peptide R3(B Delta 23-27) is a weak agonist. This suggests that the C-terminal Arg, although increasing the affinity, alters the manner in which the peptide binds to the receptor and thereby prevents activation, giving R3(B Delta 23-27)R/I5 its potent antagonistic activity.
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| 8. |
- Li, Yadi, et al.
(författare)
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Virtual and In vitro bioassay screening of phytochemical inhibitors from flavonoids and isoflavones against Xanthine oxidase and Cyclooxygenase-2 for gout treatment
- 2013
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Ingår i: Chemical Biology and Drug Design. - : John Wiley & Sons. - 1747-0277 .- 1747-0285. ; 81:4, s. 537-544
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Tidskriftsartikel (refereegranskat)abstract
- Synthetic drugs such as allopurinol and benzbroarone are commonly used to treat the complex pathogenesis of gout, a metabolic disease that results from an inflammation of the joints caused by precipitation of uric acid. We seek to discover novel phytochemicals that could treat gout, by targeting the xanthine oxidase (XO) and cyclooxygenase 2 (COX-2) enzymes. In this study, we report the screening of 9 compounds of flavonoids from the ZINC and PubChem databases (containing 2,092 flavonoids) using the iGEMDOCK software tool against the XO and COX-2 3D protein structures. Each compound was also evaluated by an in vitro bioassay testing the inhibition of XO and COX-2. Myricetin and luteolin were found to be the potential dual inhibitors of XO and COX-2 as demonstrated by IC50: 62.7 and 3.29μg/mL (XO) / 70.8 and 16.38μg/mL (COX-2), respectively. In addition, structure activity relationships and other important factors of the flavonoids binding to the active site of XO and COX-2 were discussed, which is expected for further rational drug design.
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| 9. |
- Delbro, Dick, et al.
(författare)
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The influence of opioids on urokinase plasminogen activator on protein and mRNA level in MCF-7 breast cancer cell line
- 2009
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Ingår i: Chemical Biology and Drug Design. - 1747-0277 .- 1747-0285. ; 74:4, s. 390-396
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Tidskriftsartikel (refereegranskat)abstract
- Urokinase plasminogen activator plays a key role intumor-associated processes, increasing cancer cellinvasion and metastasis, and is therefore used as amarker in cancer prognosis. In this study, we havedetermined the effect of mu-opioid receptor agonistsand antagonists on the urokinase plasminogen activatorsecretion in MCF-7 cell line. It was shown thatmu-opioid receptor agonists, such as morphine andendomorphins, greatly stimulate urokinase plasminogenactivator secretion, while naloxone andMOR-selective antagonists elicit the oppositeeffect. The same tendency was observed also onthe urokinase plasminogen activator mRNA level.However, neither agonists nor antagonists had anyeffect on proliferation of MCF-7 cells. The findingsreported in this study may be useful in designingfurther experiments aimed at elucidating the roleof the opioid system in cancer cells
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| 10. |
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