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Antimicrobial Agents and Chemotherapy, November 2007, p. 3887-3894, Vol. 51, No. 11
0066-4804/07/$08.00+0     doi:10.1128/AAC.01599-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Cyclic Tetrapyrrole Sulfonation, Metals, and Oligomerization in Antiprion Activity{triangledown}

Winslow S. Caughey, Suzette A. Priola, David A. Kocisko,{dagger}, Lynne D. Raymond, Anne Ward, and Byron Caughey*

Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, Montana 59840

Received 21 December 2006/ Returned for modification 27 February 2007/ Accepted 9 August 2007

Cyclic tetrapyrroles are among the most potent compounds with activity against transmissible spongiform encephalopathies (TSEs; or prion diseases). Here the effects of differential sulfonation and metal binding to cyclic tetrapyrroles were investigated. Their potencies in inhibiting disease-associated protease-resistant prion protein were compared in several types of TSE-infected cell cultures. In addition, prophylactic antiscrapie activities were determined in scrapie-infected mice. The activity of phthalocyanine was relatively insensitive to the number of peripheral sulfonate groups but varied with the type of metal bound at the center of the molecule. The tendency of the various phthalocyanine sulfonates to oligomerize (i.e., stack) correlated with anti-TSE activity. Notably, aluminum(III) phthalocyanine tetrasulfonate was both the poorest anti-TSE compound and the least prone to oligomerization in aqueous media. Similar comparisons of iron- and manganese-bound porphyrin sulfonates confirmed that stacking ability correlates with anti-TSE activity among cyclic tetrapyrroles.

* Corresponding author. Mailing address: RML, NIAID, 903 S. 4th St., Hamilton, MT 59840. Phone: (406) 363-9264. Fax: (406) 363-9286. E-mail: bcaughey{at}niaid.nih.gov

{triangledown} Published ahead of print on 20 August 2007.

{dagger} Present address: Department of Neurobiology, Biogen Idec, 14 Cambridge Center, Cambridge, MA 02142.

Antimicrobial Agents and Chemotherapy, November 2007, p. 3887-3894, Vol. 51, No. 11
0066-4804/07/$08.00+0     doi:10.1128/AAC.01599-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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