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Anthony Masters. Mystery at Moorsea Manor. Carolyn Keene. English Thai Joke Book. Jeremy Taylor. Oxygen dissociation curves can be used to illustrate Le Chatelier's Principle which states that a system in dynamic equilibrium responds to any stress by restoring the equilibrium. For example shifts in the position of the curve occur as a result of the concentration of CO 2 or changes in pH. Haemoglobin can also bind carbon dioxide, but to a lesser extent.
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Carbaminohaemoglobin forms. Some carbon dioxide is carried in this form to the lungs from respiring tissues. The presence of carbon dioxide helps the release of oxygen from haemoglobin, this is known as the Bohr effect. This can be seen by comparing the oxygen dissociation curves when there is less carbon dioxide present and when there is more carbon dioxide in the blood. When carbon dioxide diffuses into the blood plasma and then into the red blood cells erythrocytes in the presence of the catalyst carbonic anhydrase most CO 2 reacts with water in the erythrocytes and the following dynamic equilibrium is established.
Carbonic acid, H 2 CO 3 , dissociates to form hydrogen ions and hydrogencarbonate ions. This is also a reversible reaction and undissociated carbonic acid, hydrogen ions and hydrogencarbonate ions exist in dynamic equilibrium with one another. Inside the erythrocytes negatively charged HCO 3 - ions diffuse from the cytoplasm to the plasma. This is balanced by diffusion of chloride ions, Cl - , in the opposite direction, maintaining the balance of negative and positive ions either side. This is called the ' chloride shift '.
Lane 1, molecular mass standards; lane 2, isolated human blood plasma diluted fold; lane 3, recombinant human TTR. The higher molecular mass band in lane 3 is due to an SDS-resistant dimer present when the recombinant protein is run on a gel. Summary of the procedure to evaluate inhibitor binding selectivity to TTR versus other plasma proteins. Human blood plasma is incubated with a small molecule inhibitor black bars for 24 h. The TTR tetramer squares and bound small molecules are precipitated with antibody-conjugated Sepharose circle.
The Sepharose is washed to remove unbound proteins oval and diamond and small molecules triangle. TTR with shown here or without ligands bound is eluted at high pH. The supernatant is loaded onto an HPLC column for analysis and quantification. The early peak corresponds to a TTR monomer disulfide linked through its single cysteine residue to a single cysteine amino acid, which has been observed previously 47 — 49 , whereas the second peak corresponds to the expected TTR monomer. Inhibitors that bind to TTR in plasma elute separately on the chromatogram, e.
TTR appears as two peaks, the first peak being monomer disulfide linked to cysteine and the second peak being unconjugated monomer. Because these compounds are already approved by the Food and Drug Administration, they could easily be evaluated in human clinical trials for another indication if they proved to be selective TTR binders in human plasma. When these compounds were incubated with plasma at their maximal therapeutic concentrations, flufenamic acid and diflunisal showed increased binding selectivity stoichiometry to TTR Table 1.
Increasing the concentration of all other NSAIDs to their maximal therapeutic dose did not result in dramatic increases in binding selectivity, likely because of binding to other plasma proteins. These compounds were derived from screening or structure-based design and identified as promising by an in vitro fibril formation assay refs. Oza, H. Petrassi, and J. Lead compounds having diverse structures including biaryls, biarylamines, stilbenes, and dibenzofurans showed promising selectivity Table 2.
Three compounds from this group 9 - 11 possess excellent TTR-binding selectivity in plasma. At a concentration of Determination of the TTR-binding affinities of these three compounds in buffer shows that the K d values do not correlate with the plasma binding selectivity Table 2. For example, inhibitors 9 and 10 have greater than an order of magnitude difference in K d but nearly identical binding selectivity stoichiometry to TTR in plasma. Moreover, compounds with modest binding selectivity, such as flufenamic acid 1 , have been previously determined to have K d values very similar to those exhibiting excellent selectivities Interestingly, compound 9, synthesized by our laboratory, was initially synthesized and evaluated by Bristol—Myers and Parke—Davis as a possible antiinflammatory compound 53 , Its modest activity never warranted pursuit beyond initial animal testing.
However, this compound exhibits the highest binding selectivity stoichiometry for TTR in plasma of any compound evaluated thus far at a concentration of It is a potent TTR amyloid inhibitor in vitro , thus making it a candidate for further evaluation in animals and possibly in humans. Binding to plasma proteins is an important factor in determining the overall distribution, metabolism, activity, and toxicity of a drug In this particular case, we desire small molecules that bind to the plasma protein TTR over protein competitors whose identities are not known and likely change with the small molecule under evaluation.
This binding is known to stabilize TTR's normally folded state, thus preventing the conformational changes required for amyloidogenicity 14 , Immunoprecipitation has been used previously to determine the stoichiometry of metal ion binding to specific plasma proteins 56 , However, to our knowledge, this is the first use of the technique to determine the binding selectivity of a small molecule to a single protein in human plasma. In principle, this approach is applicable to evaluate the binding selectivity of small molecules to any plasma protein, provided that a highly selective antibody for the protein can be generated, binding does not block the epitope or destroy it by conformational change, and appropriate wash steps can be introduced to avoid nonspecific binding of the small molecule and other proteins to the resin.
The protein target s of small molecule drugs have been established in the presence of all plasma components or in whole blood in surprisingly few instances. Typically, binding is evaluated either to all plasma proteins or to an isolated suspected protein target in a standard buffer in vitro.
Equilibrium dialysis and ultrafiltration are commonly used to evaluate drug binding to whole plasma These methods provide information on the amount of compound bound to total plasma protein, but they do not identify the specific target.
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Drug binding to isolated or recombinant plasma proteins can be characterized by numerous methods such as fluorescence 58 , NMR 59 , CD or related spectroscopies 60 , chromatography 61 , 62 , calorimetry 37 , or surface plasmon resonance In contrast, the immunoprecipitation approach presented here allows one to determine the amount of small molecule bound to a specific protein in the presence of all plasma proteins and competitive ligands, without the requirement of identifying the appropriate competitor protein s.
The effect of small molecule structure on TTR binding selectivity in plasma is dramatically demonstrated in a series of biarylamines of nearly identical chemical structure Fig. Oza and J. However, these compounds exhibit dramatically different TTR binding selectivity in human plasma. Moving the Cl substituents from the 2 and 6 positions 5 to the 3 and 5 positions 13 results in a significant increase in TTR binding selectivity.