Serum Protein Proves Effective Against Trypanosomes

Researchers have combined a modified human serum protein with a miniature antibody (nanobody) to create a drug capable of curing trypanosomiasis in mice that has the potential for treating sleeping sickness in humans.

Human sleeping sickness in east Africa, which kills more than 300,000 people each year, is caused by the parasite Trypanosoma brucei rhodesiense. The basis for infection is the resistance of these parasites to lysis by proteins in normal human serum (NHS). The parasites' resistance to lysis by human serum apolipoprotein L-1 (APOL1) is conferred by a gene that encodes a truncated form of the variant surface glycoprotein called serum resistance-associated protein (SRA). SRA is a lysosomal protein, and the N-terminal alpha-helix of SRA is responsible for resistance to lysis. This domain interacts strongly with a carboxy-terminal alpha-helix of APOL1.

Investigators at the Free University of Brussels (Belgium) engineered a truncated form of APOL-I (Tr-APOL-I) by deleting its SRA-interacting domain. They then conjugated Tr-APOL-I with a single-domain antibody (nanobody) that is specific for certain conserved cryptic epitopes of the variant surface glycoprotein (VSG) of the trypanosomes. Results published in the April 9, 2006, online edition of the journal Nature Medicine showed that a single treatment with the engineered conjugate resulted in clear curative and alleviating effects on acute and chronic infections of mice with both NHS-resistant and NHS-sensitive trypanosomes.

The authors believe that this approach may yield the first truly effective drug against African sleeping sickness.



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