Heavy-metal complexation by de novo peptide design

• Published in: Current opinion in drug discovery & development Vol. 5; no. 6; p. 937
• Main Authors: Farrer, Brian T, Pecoraro, Vincent L
• Format: Journal Article
• Language: English
• Published: England 01.11.2002
• Subjects: Amino Acid Sequence; Animals; Carrier Proteins - chemical synthesis; Drug Design; Humans; Metals, Heavy - blood; Metals, Heavy - chemistry; Metals, Heavy - metabolism; Molecular Sequence Data; Peptide Biosynthesis; Peptides - chemistry; Peptides - metabolism; Technology, Pharmaceutical - methods
• ISSN: 1367-6733

From poisoning caused by lead-based paint on domestic buildings to groundwater contamination by naturally occurring arsenic deposits in India, heavy-metal toxicity is a global health problem. Contaminated ground water and acute cases of heavy-metal poisoning are treated with chelators to remove the heavy metals from the contaminated site or person. This review discusses the effort to generate heavy-metal chelators through peptide de novo design. De novo design entails the design of a primary sequence that will precisely fold into a predetermined secondary and tertiary protein structure. The first-generation peptide chelator used to initiate this investigation is the three-stranded coild coil containing Cys. Cys provides a potential trigonal binding site with soft thiolate ligands, which has been proposed to provide specific interactions with heavy metals. This hypothesis derives from the observation that similar sites on natural proteins show selectivity for heavy metals over other essential metals, such as Zn or Mg. A description of two systems, the TRI series and the IZ-AC peptide, is given, highlighting the interaction of these peptides with Hg, Cd, As and Pb. Arguments are also presented for the potential use of three-helix bundles as a second-generation design.