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Antimicrobial Agents and Chemotherapy, May 2007, p. 1700-1707, Vol. 51, No. 5
0066-4804/07/$08.00+0     doi:10.1128/AAC.01555-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Immunomodulatory Peptide from Cystatin, a Natural Cysteine Protease Inhibitor, against Leishmaniasis as a Model Macrophage Disease

Molecular Cell Biology Laboratory, Indian Institute of Chemical Biology, Calcutta, India

Received 15 December 2006/ Returned for modification 3 February 2007/ Accepted 22 February 2007

Cystatin, a natural cysteine protease inhibitor, has strong antileishmanial activity, which is due to its potential to induce nitric oxide (NO) generation from macrophages. Cysteine protease-inhibitory activity and NO-up-regulatory activity correspond to different regions, as revealed by the dissection of cystatin cDNA into nonoverlapping fragments. By using synthetic overlapping peptides, the NO-up-regulatory activity was found to be confined to a 10-mer sequence. In addition to having reasonable inhibitory effects on amastigote multiplication within macrophages (50% inhibitory concentration, 5.2 µg/ml), 97 and 93% suppression, respectively, of liver and spleen parasite burdens was achieved with the 10-mer peptide at a dose of 0.5 mg/kg of body weight/day, given consecutively for 4 days along with a suboptimal dose of gamma interferon in a 45-day mouse model of visceral leishmaniasis. Peptide treatment modulated the levels of cytokine secretion by infected splenocytes, with increased levels of interleukin-12 and tumor necrosis factor alpha and increased inducible NO synthase production, and also resulted in resistance to reinfection. The generation of a natural peptide from cystatin with robust immunomodulatory potential may therefore provide a promising therapeutic agent for macrophage-associated diseases.

Published ahead of print on 5 March 2007.