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Protease Inhibitors and Prohormone Processing
- Ann Danoff, MD; and
- Wai Lam W. Ling, PhD
- Bronx-Lebanon Hospital Center; Bronx, NY 10457 (Danoff) Schering-Plough Research Institute; Union, NJ 07083 (Ling)
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IN RESPONSE:
We appreciate Stricker and Goldberg's comments on the distinctive substrate specificities of aspartic and serine proteases. We agree it is unlikely that inhibitors of an aspartyl protease, such as the HIV protease inhibitors, would interfere with proteolytic events usually performed by serine proteases, such as the prohormone-converting enzymes. However, several examples of nonstringent prohormone processing events have been reported. In particular, evidence suggests that the yeast aspartyl protease, Yap3, is capable of accurate endoproteolysis of both prosomatostatin (1) and proopiomelanocortin (2), functions usually performed by the prohormone convertases. In addition, as noted in a previous correspondence between Stricker and Goldberg and other investigators (3), broad substrate specificity for the HIV protease has been inferred from statistical analysis of an extended database (4). In view of these reports of functional overlap between serine and aspartic proteases (and perhaps their inhibitors) and clinical observations suggestive of insulin resistance, we and others (5) felt it was reasonable to investigate the possibility that protease inhibitor therapy was interfering with prohormone processing.
We feel confident with our conclusion that, when used as single agents, HIV protease inhibitors do not directly interfere with prohormone processing in vitro, and agree with Stricker and Goldberg that alternative mechanisms should be explored. Further investigation, including studies aimed at elucidating the role of protease inhibitor–induced cathepsin inhibition or nucleoside analogue–induced mitochondrial toxicity, alone or in combination, and exploration of alternative hypotheses are welcome.
Wai Lam W. Ling, PhD
Schering-Plough Research Institute; Union, NJ 07083
The Editors welcome submissions for possible publication in the Letters section. Authors of letters should:
•Include no more than 300 words of text, three authors, and five references
•Type with double-spacing
•Send three copies of the letter, an authors' form signed by all authors, and a cover letter describing any conflicts of interest related to the contents of the letter.
Letters commenting on an Annals article will be considered if they are received within 6 weeks of the time the article was published. Only some of the letters received can be published. Published letters are edited and may be shortened; tables and figures are included only selectively. Authors will be notified that the letter has been received. If the letter is selected for publication, the author will be notified about 3 weeks before the publication date. Unpublished letters cannot be returned.
Annals welcomes electronically submitted letters.
- Copyright ©2004 by the American College of Physicians
