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[C&EN, July 16, 2001]

[C&EN, June 18, 2001]

[C&EN, Apr. 9, 2001]

Detecting Prions
[C&EN, Apr. 9, 2001]

Detecting Prion Strains
[C&EN, Oct. 5, 1998]

Prion Protein's Role Revealed
[C&EN, Sep. 18, 2000]

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Fred E. Cohen

R. Anthony Williamson

Dennis R. Burton

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ACS Seeks A Society Secretary

American Chemical Society Secretary Halley A. Merrell has announced his plans to retire at the end of this year. The society has opened a search to replace him. The position is advertised in this week's C&EN Classified section on page 80. (Applications must be received by Sept. 20). Merrell has been with ACS for 38 years; he became ACS secretary in 1998.

The society secretary is the secretary of the board of directors and the council and is the main liaison with the board and various governance units.

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August 20
, 2001
Volume 79, Number 34
CENEAR 79 34 p. 11
ISSN 0009-2347
[Previous Story] [Next Story]

One antiprion agent already is being used to treat human patients


Therapies for fighting prion diseases are beginning to emerge, and one agent is already being used to treat people. Prions are infectious proteins believed to cause mad cow disease, Creutzfeldt-Jakob disease (CJD) in humans, and related fatal conditions for which there currently are no treatments.

"The results we saw, in a cell model we consider valid, make this lead worth pursuing immediately."

–Carsten Korth

Postdocs Carsten Korth and Barnaby C. H. May, professor of medicine and pharmacology Fred E. Cohen, and neurology and biochemistry professor Stanley B. Prusiner of the University of California, San Francisco, have rediscovered two approved tricyclic drugs--the antimalarial agent quinacrine and the antipsychotic chlorpromazine--and have confirmed that they inhibit prion infection in cells [Proc. Natl. Acad. Sci. USA,
98, 9836 (2001)].

Clinical trials in human CJD patients are planned for both drugs, individually and in combination, and quinacrine is already being administered to two patients on a compassionate-use basis, one of whom has reportedly improved markedly.

Prusiner and coworkers identified the drugs independently and found that they inhibit conversion of normal prion protein into infectious prions and clear prions from infected cells. Both drugs can cross over from the bloodstream to the brain, where prion diseases are localized. Chlorpromazine crosses the blood-brain barrier more readily than quinacrine, but quinacrine is 10 times more potent.

But after they identified the drugs, the UCSF researchers found that chlorpromazine's effects on prion formation had actually been reported in two mid-1980s studies and that quinacrine's antiprion activity in cells had been discovered by associate professor of neuropathology Katsumi Doh-ura of Kyushu University, Fukuoka, Japan; prion researcher Byron Caughey of Rocky Mountain Laboratories, Hamilton, Mont.; and Toru Iwaki [J. Virol., 74, 4894 (2000)].

In Japanese animal trials, quinacrine has shown little efficacy in delaying the onset of symptoms after infection, Doh-ura tells C&EN. But it could be more effective against human prion disease or in combination with chlorpromazine, he says.

In other work, assistant professor R. Anthony Williamson and professor Dennis R. Burton of the immunology department at Scripps Research Institute, and coworkers, including Prusiner, found antibody fragments that bind prion protein and dose-dependently block prion formation in cells [Nature, 412, 739 (2001)]. With one such antibody agent, prion replication was abolished and prions were eliminated, "suggesting that this antibody may cure established infection."

"The Nature paper is a very nice scientific study, but the results aren't all that surprising," comments prion researcher Suzette A. Priola of Rocky Mountain Labs. She notes that an antibody that inhibits prion formation had also been identified earlier by Caughey and a coworker [EMBO J., 18, 3193 (1999)] and that Prusiner's group had already reported that an antibody could neutralize some prion infectivity [Proc. Natl. Acad. Sci. USA, 85, 6617 (1988)].

Prion researcher Charles Weissmann and coworkers of the Imperial College School of Medicine at St. Mary's, London, also reported last month that an antibody prevents prions from infecting cells and cures chronically infected cells [Proc. Natl. Acad. Sci. USA, 98, 9295 (2001)], suggesting "that passive immunization may provide a therapeutic approach to prion disease." But Weissmann cautions that "it will not be trivial to achieve the necessary antibody levels in the brain" and that effects of antibody agents in brain tissue may not match those in cell culture.

Nevertheless, one or more tricyclic drugs and antibody agents "may very well end up being effective in vivo," Priola says."This is certainly a possibility."


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