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IF YOU fail to respond to a drug, it could be because your body is smashing it up without so much as a hello. Scientists have known for some time now that this happens particularly with drugs that mimic proteins. These drugs usually occur in 2 molecular forms -- one is extremely active but is easily chewed up by the body's enzymes; the other is resistant to the body's digestive juices but is less enthusiastic against disease.
Now scientists at the Thomas Jefferson University in Philadelphia, USA, have devised a novel drug design, which endows the active form of a drug with resistance to the body's trigger-happy assault team (Nature, Vol 368, No 6473).
Protein-like drugs comprise amino acids -- the basic building blocks of protein molecules -- that occur in 2 forms, the "L" and "D" forms. These forms have the same atoms but different orientation, with one being a mirror image of the other.
Interestingly, all the naturally occurring amino acids and the proteins they make up are found only in the L form; enzymes like proteases, which break down these proteins, only recognise L proteins. But these L-form proteins are also the most effective as drugs because they are easily recognised and welcomed by the body tissues on which they act. The D form of proteins or of peptides -- small protein chains -- are resistant to being broken down by enzymes, making them ideal as drugs, but they are inhibited because the tissues in the body are not programmed to recognise them.
Thomas Jefferson University scientists led by B A Jameson have, for the first time, constructed in the laboratory -- through sophisticated computer modelling and synthetic chemical pathways -- a hybrid molecule that can resist the body's enzymes as well as act effectively on the target. This peptide inhibits both the clinical incidence and severity of experimental allergic encephalomyelitis (EAE), an acute inflammatory disease of the central nervous system. EAE is manifest in mice, but is also used as a model for multiple sclerosis, a similar disease that affects the nervous system of human beings, leading to paralysis.
The scientists targeted a particular peptide of a key protein in the immune system of the diseased individual, which affects the nervous tissue. They figured that if they could mimic this protein, the body could then be induced to knock out the offending natural protein by its own antibodies -- chemicals produced by the body in response to foreign organisms or chemicals -- much the same way as a vaccine works. It was, however, important that the mimicked protein was not digested by the enzymes present in the serum.
The scientists found that the synthetic peptide containing L-amino acids could not induce an antibody response, because it was quickly digested by the body's enzymes. Jameson and his colleagues, using advanced computer software, then modelled a particular peptide: then the chemical groups responsible for the peptide's activity are maintained in the L form, while the orientation of the other atoms was altered, making it resistant to enzyme action. They found that this peptide was active and its effects were manifest even after the appearance of disease symptoms.
This new technique, say scientists Guy Dodson of the University of York and Leo Brady of the University of Bristol, both in the UK, opens up a new interface between synthetic chemistry and molecular biology and will have a considerable impact on drug design.