Antigen-Presenting Cell Interdomain B MHC Complex
Commercially viable HC1 recycling can help producers of polyurethanes, isocyanates, pigments, and various other compounds avoid having to dispose of T-cell toxic and corrosive HC1 waste by-prodreceptor ucts while simultaneously having to purchase virgin chlorine for continued manufacturing. \ Catalytic The scientists say their method, a Domain two-stage version of a process invented Interdomain A l^. TCell more than a century ago, could allow industry to reduce chlorine consumption by 25 to 33%, greatly reducing the amount of chlorine shipped by road, rail, and waterways. //r The process looks like an interesting new approach to HC1 [recycling], an imZAP-70 bound to £ subunit of activated T-cell receptor. T-cell receptor activation occurs when portant environmental problem,,, says receptor's a and (3 subunits bind to an antigenic peptide associated with the major histoE. Manzer, director of DuPont's corcompatibility complex (MHC) on an antigen-presenting cell ZAP then binds (via its twoLeo SH2 porate catalysis center in Wilmington, Del. domains) to the activated (phosphorylated) £ peptide. Ariad researchers find that two phosphorylated tyrosines (red) and two leucines (yellow) on C, are primary determinants of ZAP-70 Many technologies exist for recycling binding—that is, these residues can't be modified without greatly weakening the interaction. HC1 into Cl2, such as electrolysis, direct oxidation with inorganic oxidation agents, ing site for £, instead of binding inde- combinatorial chemistry strategies in an and oxidation of HC1 by oxygen in the pendently to it as some researchers had effort to develop new small-molecule presence of a catalyst. However, those previously believed. (nonpeptide) immunosuppressants. processes are expensive and inefficient. The method developed at USC imAriad is seeking to develop drugs that They already have in hand a series of block the interaction between ZAP and cell-permeable compounds that are spe- proves on the Deacon process, patented in the T-cell receptor and thus suppress im- cific to ZAP, bind to its SH2 domains, 1868, which uses copper chloride to catalyze the oxidation of HC1 by oxygen at mune reactions. Such immune system and interrupt T-cell activation. regulatory drugs are needed to treat The company plans to use the new in- temperatures of 430 to 475 °C to produce autoimmune diseases like rheumatoid formation on the structure of the ZAP/ Cl2. The Deacon process recovers about arthritis, multiple sclerosis, and inflam- receptor complex to further improve 70% of waste chlorine atoms, but the heat matory bowel disease. The current gen- these lead compounds and to identify causes evaporation of the copper chloride, eration of immunosuppressants—cyclo- additional ZAP inhibitors. It plans to be- and unreacted HC1 mixes with water sporin A and FK506 (tacrolimus)—have gin testing irnmunosuppressive ZAP in- during the reaction, leading to corrosion. powerful side effects that limit their use hibitors in animal models for autoimOther scientists have attempted to overfor the most part to curbing the immune mune disease later this year. come these difficulties, but have been styreactions responsible for organ transStu Borman mied by problems of inefficient catalyst plant rejection. systems or poor reactor conditions. The USC group has been working on Cyclosporin A and FK506 inhibit calimproving the Deacon process since 1989. cineurin, another enzyme in the T-cell Their method involves first reacting signaling pathway (C&EN, Aug. 14, HC1 over a fluidized bed of copper oxpage 7). Harvard University chemistry ide at about 200 °C to produce a copper professor Stuart L. Schreiber, a founder of Ariad, explains: "ZAP is several mol- A new method of recycling hydrogen chloride complex and water. Then the ecules upstream of calcineurin, and it chloride (HC1) into molecular chlorine fluidized copper chloride complex is regulates calcineurin's activity. Unlike (Cl2) has now been shown to be eco- transported to a second reactor, where calcineurin, which is broadly expressed, nomically viable for industry, with the oxygen is passed over it at 360 °C. The ZAP is found exclusively in T cells [and potential to save chemical manufacturers copper chloride is oxidized back to copnatural killer cells]. Humans with a ge- millions of dollars while reducing envi- per oxide, and chlorine is released [Ind. netic defect in ZAP have a lack of im- ronmental risks, according to the Cali- Eng. Chem. Res., 33,2996 (1994)]. mune function, but none of the charac- fornia chemists who developed it. The scientists have received various teristic toxicities that result from inhibitAfter recent pilot-scale testing, chemical patents on the technology and have been ing calcineurin—for example, neuronal engineering professors Ronald G. Minet running a study at a pilot plant at the dysfunction from calcineurin inhibition and Theodore T. Tsotsis and emeritus Zona Franca plant of Carburos Metalicos in the brain and kidney dysfunction chemistry professor Sidney W. Benson, in Barcelona, Spain. They say the process from calcineurin inhibition in renal tu- all at the University of Southern Califor- will recover chlorine from waste HC1 for bule cells. These effects are seen with nia, Los Angeles, have determined the less than $80 per ton—compared with a both cyclosporin and FK506." technology could recover nearly 100% of cost of about $200 per ton for virgin Ariad researchers are pursuing com- chlorine atoms from HC1 for less than a chlorine. plementary structure-based design and third of the cost of new Cl2. Elizabeth Wilson Antigen
New process recycles HC1 into chlorine
SEPTEMBER 11,1995 C&EN
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