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991.
Nicola A. G. Meenan Amit Sharma Sarel J. Fleishman Colin J. MacDonald Bertrand Morel Ruth Boetzel Geoffrey R. Moore David Baker Colin Kleanthous 《Proceedings of the National Academy of Sciences of the United States of America》2010,107(22):10080-10085
High-affinity, high-selectivity protein-protein interactions that are critical for cell survival present an evolutionary paradox: How does selectivity evolve when acquired mutations risk a lethal loss of high-affinity binding? A detailed understanding of selectivity in such complexes requires structural information on weak, noncognate complexes which can be difficult to obtain due to their transient and dynamic nature. Using NMR-based docking as a guide, we deployed a disulfide-trapping strategy on a noncognate complex between the colicin E9 endonuclease (E9 DNase) and immunity protein 2 (Im2), which is seven orders of magnitude weaker binding than the cognate femtomolar E9 DNase-Im9 interaction. The 1.77 Å crystal structure of the E9 DNase-Im2 complex reveals an entirely noncovalent interface where the intersubunit disulfide merely supports the crystal lattice. In combination with computational alanine scanning of interfacial residues, the structure reveals that the driving force for binding is so strong that a severely unfavorable specificity contact is tolerated at the interface and as a result the complex becomes weakened through “frustration.” As well as rationalizing past mutational and thermodynamic data, comparing our noncognate structure with previous cognate complexes highlights the importance of loop regions in developing selectivity and accentuates the multiple roles of buried water molecules that stabilize, ameliorate, or aggravate interfacial contacts. The study provides direct support for dual-recognition in colicin DNase-Im protein complexes and shows that weakened noncognate complexes are primed for high-affinity binding, which can be achieved by economical mutation of a limited number of residues at the interface. 相似文献
992.
Amit K. Tiwari Si-Rong Wang Charles R. Ashby Jr. Zhe-Sheng Chen 《Biochemical pharmacology》2009,78(2):153-11
Nilotinib, a BCR-Abl tyrosine kinase inhibitor (TKI), was developed to surmount resistance or intolerance to imatinib in patients with Philadelphia positive chronic myelogenous leukemia. Recently, it was shown that several human multidrug resistance (MDR) ATP-binding cassette (ABC) proteins could be modulated by specific TKIs. MDR can produce cancer chemotherapy failure, typically due to overexpression of ABC transporters, which are involved in the extrusion of therapeutic drugs. Here, we report for the first time that nilotinib potentiates the cytotoxicity of widely used therapeutic substrates of ABCG2, such as mitoxantrone, doxorubicin, and ABCB1 substrates including colchicine, vincristine, and paclitaxel. Nilotinib also significantly enhances the accumulation of paclitaxel in cell lines overexpressing ABCB1. Similarly, nilotinib significantly increases the intracellular accumulation of mitoxantrone in cells transfected with ABCG2. Furthermore, nilotinib produces a concentration-dependent inhibition of the ABCG2-mediated transport of methotrexate (MTX), as well as E217βG a physiological substrate of ABCG2. Uptake studies in membrane vesicles overexpressing ABCG2 have indicated that nilotinib inhibits ABCG2 similar to other established TKIs as well as fumitremorgin C. Nilotinib is a potent competitive inhibitor of MTX transport by ABCG2 with a Ki value of 0.69 ± 0.083 μM as demonstrated by kinetic analysis of nilotinib. Overall, our results indicate that nilotinib could reverse ABCB1- and ABCG2-mediated MDR by blocking the efflux function of these transporters. These findings may be used to guide the design of present and future clinical trials with nilotinib, elucidating potential pharmacokinetic interactions. Also, these findings may be useful in clinical practice for cancer combination therapy with nilotinib. 相似文献
993.
994.
995.
Hongliang Cai Arun K. Agrawal David A. Putt Muhammed Hashim Anita Reddy Joanne Brodfuehrer Narayanan Surendran Lawrence H. Lash 《Toxicology》2009
PF1, an anti-inflammatory drug candidate, was nephrotoxic in cynomolgus monkeys in a manner that was qualitatively comparable to that observed with the two previous exploratory drug candidates (PF2 and PF3). Based on the severity of nephrotoxicity, PF1 ranked between the other two compounds, with PF2 inducing mortality at all doses and PF3 eliciting only mild nephrotoxicity. To further characterize nephrotoxicity in monkeys and enable direct comparisons with humans, primary cultures of proximal tubular (PT) cells from monkey and human kidneys were used as in vitro tools, using lactate dehydrogenase release as the biomarker of cytotoxicity. In both human and monkey PT cells, PF2 was by far the most cytotoxic compound of the three drugs. PF1 exhibited modest cytotoxicity at the highest concentration tested in human PT cells but none in monkey kidney cells whereas PF3 exhibited the reverse pattern. Because these drugs are organic anions, mechanistic studies using human organic anion transporters 1 and 3 (hOAT1 and hOAT3) transfected cell lines were pursued to evaluate the potential of these compounds to interact with these transporters. All three drugs exhibited high affinity for hOAT3 (PF1 exhibited the lowest IC50 of 6 μM) but only weakly interacted with hOAT1 (with no interaction found for PF2). PF2 was a strong hOAT3 (not hOAT1) substrate, whereas PF1 and PF3 were substrates for both hOAT1 and hOAT3. Upon pretreatment of monkeys with the OAT substrate probenecid, PF3 systemic exposure (AUC) and half-life (t1/2) increased ∼2-fold whereas clearance (CL) and volume of distribution (Vdss) decreased, as compared to naïve monkeys. This indicated that PF3 competed with probenecid for hOAT1 and/or hOAT3 mediated elimination of PF3. Thus, hOAT1 and/or hOAT3 may be responsible for the uptake of this series of drugs in renal PT cells, which may directly or indirectly lead to the observed nephrotoxicity in vivo. 相似文献
996.
Abha Agrawal Jeffrey K Aronson Nicky Britten Robin E Ferner Peter A de Smet Daniela Fialová Richard J Fitzgerald Robert Liki? Simon R Maxwell Ronald H Meyboom Pietro Minuz Graziano Onder Michael Schachter Giampaolo Velo Members of EMERGE the Erice Medication Errors Research Group the Erice Medication Errors Research Group 《British journal of clinical pharmacology》2009,67(6):592-598
997.
Many sub-unit vaccines are successful in preventing the occurrence of disease, but their use is largely restrained due to low immunogenicity. Novel carrier-based vaccine could serve as a vaccine adjuvant to overcome low immunogenicity of sub-unit vaccines. The use of liposomes as a delivery system for antigen is well recognized but they are unstable and release of antigen from them cannot be controlled over a prolonged period of time. To overcome the limitation of liposomes, this study has developed gel core liposomes in which a core of polymer was incorporated inside the liposomal vesicles, which serve the function of skeleton and provide mechanical strength to vesicles. In the present investigation BSA-loaded gel core liposomes were prepared by reverse phase evaporation method and characterized for vesicles size, shape, entrapment efficiency, in vitro release and stability studies. The in vivo studies to evaluate antigen presenting potential of the gel-core liposomes was performed in Balb/c mice by measuring the immune response elicited by intramuscular administration of BSA-loaded gel core liposomes and compared with intramuscularly administered BSA-loaded conventional liposomes, alum adsorbed BSA and plain antigen. Results indicate that intramuscular immunization with gel core liposomes induces efficient systemic antibody responses against BSA as compared to other formulations. The gel core liposomal formulation provides good entrapment efficiency, enhanced in vitro stability, prolonged antigen release and effective immunoadjuvant property, justifying its potential for improved vaccine delivery. 相似文献
998.
Simon Gaisford Amit Verma Mark Saunders Paul G. Royall 《International journal of pharmaceutics》2009,380(1-2):105-111
The aim of this study was to evaluate the potential of isothermal calorimetry to monitor and characterize crystallisation in drug-loaded fast-dissolving oral films.Films of polyvinylpyrrolidone (PVP) containing indomethacin were cast into glass ampoules; stability was assessed by monitoring the power changes occurring with time. Three grades of PVP (K10, K25 and K40, where the number multiplied by 1000 gives the average molecular weight) were used. Indomethacin was seen to crystallise from all PVP grades over ca. 24–48 h at two study temperatures (25 and 37 °C), as denoted by a large exothermic event. At 25 °C the exothermic event was a single peak; at 37 °C two peaks were observed. Subsequent analysis of the crystals with differential scanning calorimetry (DSC) and polarized light microscopy determined that the stable γ-polymorph of indomethacin formed at 25 °C while both the γ- and metastable α-polymorphs formed at 37 °C. The calorimetric data were converted to relative crystallinity as a function of time and analysed with three crystallisation models (Avrami, Tobin and Urbanovici–Segal) to determine crystallisation kinetics. Of the three models applied the Urbanovici–Segal model best described the data, although this may be because this model contains a term that effectively accounts for deviation from the Avrami model. The rate constants determined were broadly consistent irrespective of the model used. Increasing polymer molecular weight did not generally affect the crystallisation rate, although an increase in temperature did result in a concomitant increase in crystallisation rate. The data suggest that isothermal calorimetry is able to monitor drug crystallisation in polymer films and therefore the technique could be a useful tool for conducting stability assays for fast-dissolving oral medicines. 相似文献
999.
1000.
Kawedia JD Jiang M Kulkarni A Waechter HE Matlin KS Pauletti GM Menon AG 《The Journal of pharmacology and experimental therapeutics》2008,326(3):829-837
Hg(2+) is commonly used as an inhibitor of many aquaporins during measurements of transcellular water transport. To investigate whether it could also act on the paracellular water transport pathway, we asked whether addition of Hg(2+) affected transport of radiolabeled probes through tight junctions of a salivary epithelial cell monolayer. Inclusion of 1 mM Hg(2+) decreased transepithelial electrical resistance by 8-fold and augmented mannitol and raffinose flux by 13-fold, which translated into an estimated 44% increase in pore radius at the tight junction. These Hg(2+)-induced effects could be partially blocked by the protein kinase A (PKA) inhibitor N-[2-((p-bromocinnamyl) amino) ethyl]-5-isoquinolinesulfonamide, 2HCl (H89), suggesting that both-PKA dependent and PKA-independent mechanisms contribute to tight junction regulation. Western blot analyses showed a 2-fold decrease in tight junction-associated occludin after Hg(2+) treatment and the presence of a novel hyperphosphorylated form of occludin in the cytoplasmic fraction. These findings were corroborated by confocal imaging. The results from this study reveal a novel contribution of the PKA pathway in Hg(2+)-induced regulation of tight junction permeability in the salivary epithelial barrier. Therapeutically, this could be explored for pharmacological intervention in the treatment of dry mouth, Sj?gren's syndrome, and possibly other disorders of fluid transport. 相似文献