endorphin itself, from a mixture of pig hypothalamus and pituitary tissue (C&EN, Aug. 16, page 18). One of these, called «-endorphin, has a composition corresponding to sequence 61 through 76 of β-lipotropin. It has an analgesic and tranquilizing effect in animals. The other fragment, called γ-endorphin, consists of 17 amino acids identical with β-lipotropin's 61-to-77 segment. Injected into rats, γ-endorphin induces violent behavior. Meanwhile, Li turned his attention to the 61-to-91 amino acid sequence fraction of human β-lipotropin. Working with David Chung and Dr. Byron A. Doneen, he subjected acid acetone extracts from 1000 human pituitary glands to chroma tographic separation, gel filtration, and paper electrophoresis [Biochem. Biophys. Res. Commun., 72, 1542 (1976)]. The fraction has an amino acid composition and sequence closely matching that of camel β-endorphin. The only difference is that human ^-endorphin has a tyrosine residue (instead of histidine) at position 27, and a glutamic acid (instead of glutamine) at the terminal position 31. The synthetic homolog prepared by Li and Dr. Donald Yamashiro has physical charac teristics identical to those of the naturally occurring human product. Both also have the same high degree of analgesic activity. In vivo evaluations were performed by Dr. Horace H. Loh and Dr. Liang-Fu Tseng at UC San Francis co's pharmacology and psychiatry de partments. In the standard tail-flick test on mice, for instance, human ^-endorphin has more than 48 times the potency of morphine when injected directly into the brain. Intravenous injections have a po tency better than three times that of morphine. Moreover, activity is blocked by naloxone, a specific opiate antago nist. Li theorizes that the reason methio nine-enkephalin fails to show in vivo ac tivity is that it undergoes rapid break down in the body. It's possible that the functional amino acid sequence in βendorphin responsible for the opiate re sponse is protected by folds in the longer polypeptide chain. For Li, the most recent discovery, al though extremely interesting and poten tially of great practical significance, is yet another aspect of pituitary β-lipotropin, which has fascinated him for many years. "It is a marvelous molecule," he profess es. Li now has identified four distinct physiological functions that can be traced directly to the polypeptide. The l-to-58 sequence (7-lipotropin), like its parent β-lipotropin, has fat mobilizing activity. Sequence 41 to 58 (β-melanotropin) plays a role in skin pigmentation by stimulating the melanocytes. Now, sequence 61 to 91 (^-endorphin) has proved to have both analgesic and psychopharmacological effects. It's not beyond the bounds of possibility, Li suggests, that further physiological responses might eventually be traced to other specific regions of the molecule. Dermot A. O'Sullivan, C&EN London
Antiviral chemotherapy posts slow gains In the fight against viral diseases, che motherapy hasn't been spectacularly successful to date. The fight continues, however, and progress is slowly being made. At the 16th Interscience Confer ence on Antimicrobial Agents and Che motherapy, held last month in Chicago, scientists described several advances. For example, Dr. Harry B. Greenberg of Stanford University's medical center revealed that he and associates there have been treating chronic hepatitis Β virus infections successfully with interferon, an antiviral protein produced by the body's defense system. As many as 1 million people in the U.S. may be infected by the virus, which is transmitted by blood transfusions and by the use of unsterile needles for injections. Some 10% of those who develop acute hepatitis Β become carriers. The virus and its antigens remain indefinitely in their blood and liver. They may feel well, and not know they are infected, but they can transmit the infection to others. At Stanford, four patients with differ ent degrees of chronic hepatitis Β virus infection were selected for treatment with interferon. Before treatment, the blood of each patient contained not only the viral antigen but also the so-called "Dane particles," believed to be complete hepa titis Β viruses. Daily injections of interferon signifi cantly reduced levels of Dane particles in all patients. In two patients treated for a month or more, the particles disappeared and remained absent after treatment was stopped. The same two patients later were restarted on interferon. One has now been treated for eight months, the other for four months, both without ill effects. Interferon also suppressed viral anti gen, but more slowly. During the course of treatment, biopsies revealed disappear ance of detectable viral antigen in the liver; amounts of antigen in the blood dropped to a low level. Liver disease, where apparent, seemed to improve. Although interferon appears to sup press production of Dane particles and viral antigen, it remains to be shown whether these effects will be valuable in limiting carrier infectivity or eradicating chronic infection, the Stanford workers say. They emphasize that their findings are preliminary; further testing will be required before interferon can be con sidered for general use. In any event, interferon is currently very scarce and very expensive. The only present source is human white blood cells. Some drug companies are beginning to produce the substance from human cells grown in the laboratory, Greenberg notes, so the drug may become more plentiful and less expensive. Interferon for the Stanford study was furnished by the Na tional Institute of Allergy & Infectious Diseases, which has supported much of the center's antiviral research. Development of antiviral drugs has followed two main approaches, according
to Dr. Jeannine A. Majde and Dr. Paul Gordon, both of Loyola University's Stritch School of Medicine, Maywood, 111. One approach, influenced by principles derived from antibacterial chemotherapy, has yielded antimetabolites that inhibit virus production. However, Majde and Gordon maintain, this approach hasn't yet turned up a drug that doesn't also in hibit host cell functions intolerably. A newer approach, they say, is to find drugs that stimulate the host defense system to contain or eradicate infectious agents. Such "prohost" drugs may not inhibit virus production as effectively as antimetabolites do, but they are far less toxic to the patient. Examples of such antiviral drugs are inosiplex, which stimulates host synthesis of new proteins, and levamisole, which increases signals leading to enhanced di vision of defensive cells, Majde and Gor don say. Another compound, developed by Gordon, that may have "prohost" ac tivity is l,2-0-isopropylidene-3-0-3'(N', N'- dimethyl-amino-rc -propyl) -Dglucofuranose, called SM-1213. Earlier studies in Gordon's laboratory had shown that SM-1213 had antiviral and antitumor activity. Since the body's immune system plays an important role in both instances, it seemed appropriate to study the effect of SM-1213 on immune reactivity. Mice immunized with human red blood cells were given daily doses of SM-1213. Two and four weeks after immunization, the mice were "challenged" with the same antigen, inoculated subcutaneously in one hind paw. Early and late immune re sponses were evaluated in terms of the paw-swelling that occurred at various times after the challenge. The results were that the immediate response was "strikingly depressed," compared to the response in untreated controls, while the delayed swelling re sponse was "substantially enhanced." According to Majde and Gordon, SM1213 is the first drug of its class that se lectively enhances one type of immune response while suppressing another. Majde notes that the immediate re sponses are typical of allergic or "serum sickness" reactions, both mediated pri marily by serum antibodies. The delayed swelling responses are considered evi dence of cell-mediated immunity. Al though such delayed hypersensitivity can contribute to disease (in tuberculosis, for example), it is also thought to represent a type of immunity essential to recovery from many microbial infections. The Loyola scientists also note that administration of mannose concurrently with SM-1213 further suppressed imme diate reactions but antagonized en hancement of the delayed reactions. This interaction suggests that SM-1213 may influence the process by which proteins add on essential sugars, they say, pointing out that all known soluble mediators of immunity are glycoproteins. D Nov. 15, 1976 C&EN
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