Strong synthetic inhibitors of anthrax lethal toxin

摘要

Bacillus anthracis has long been of concern as a pathogen with the potential to be used in biological warfare.After the dramatic events of the year 2001 public health authorities had been increasing research and development efforts on anthrax.Combinatorial libraries of peptides can be an important source of specific anti-toxin ligands for the treatment of anthrax intoxication.Here,we describe the production of peptides that interfere with the assembly of the toxic complex(Lethal Toxin)responsible of the severest damages produced by B.anthracis.Anthrax Lethal Toxin is composed by Protective Antigen(PA)and Lethal Factor(LF).PA is a 83 kDa protein that upon binding to a cellular receptor(Anthrax Toxin Receptor),is proteolyticalfy activated by a furin-like protease.Proteolytic removal of the N-terminus 20 kDa fragment allows the remaining receptor-bound portion(PA63)to oligomerize into a heptameric ring.The heptamer is able to bind LF and traslocate it into the cytosol.LF is a Zn-dependent metalloprotease that cleaves members of the mitogen-activated protein kinase kinase(MEKs),leading to inhibition of several cell signalling pathways.LF produces the major damages to the infected individual,with a high incidence of death.For this reason LF itself and the complex formed by PA and LF are the main targets of therapeutic agents presently studied world-wide.The synthesis of tetrabranched peptides(Multiple Antigen Peptide;MAP),whose sequences were obtained by combination of random selection and rational reconstruction,allowed to obtain a stable drug,capable to neutralize anthrax lethal action in vivo.