Outdoors, it's pollen or bee-sting. Indoors, it's house dust or catdander. There's no hiding place from the infinitude of antigensthat touch off the watery, itchy eyes, runny nose and wheezychest of allergy and asthma.
Like the weather, everybody talks about allergy, but nobodydoes anything much about it (except for antihistamines). Thatwill change if microbiologist Joan Brugge, scientific director ofAriad Pharmaceuticals Inc., has her way.
Today's issue of Science, under the rubric "Perspectives,"carries an over-the-horizon view by Brugge titled "NewIntracellular Targets for Therapeutic Drug Design." In it, shespells out how intracellular targets plus structure-basedmolecular design will in future create new pharmaceuticals.
Two weeks ago, she told a science symposium at the annualmeeting of the Massachusetts Biotechnology Council how theCambridge, Mass.-based company is exploiting biotechnologyand structure-based drug discovery to cut the allergy cascadeoff at the pass -- that is, inside the cell.
Traditionally and to date, she pointed out, drug discovery relieson randomly screening natural or man-made products "forsubstances that interfere with biological events associated withdisease." But beginning a decade ago, biotechnology has begunto identify key proteins and cellular pathways responsible fordisease. She and her team at Ariad are looking at the structureof those interacting components, to design drugs based on aknowledge of their precise atomic components.
The name of their game is signal transduction, whereby anexternal ligand (say, pollen antigen) stimulates the cell-surfaceend of a receptor (say, immunoglobulin E), which transmits amessage through the basal or mast cell membrane to itsinternal tail. From there, a second signal sets off a multiplecascade of events by sending out molecules to connect withintracellular targets that activate (in the case of allergy) suchresponses as histamine, arachidonic acid, leukotrienes,prostaglandins and cytokines.
Allergy aside, hormones, adhesion molecules andneurotransmitters are typical extracellular triggers of signaltransduction, for maintaining steady-state health, or provokingdisease.
Brugge declared that such tools as X-ray crystallography,nuclear magnetic resonance spectroscopy, peptide libraries andcomputational modeling are elucidating the fine moleculararchitecture of the signal-transduction system, to a point where"it is now feasible to develop rationally designed drugs thatspecifically interfere with the critical molecular interactionsthat underlie disease processes."
She told BioWorld that she believes that Ariad's structure-based drug-development program gives it a "head start" overother companies in the field, which are still pursuing drugdiscovery by screening alone. Harvey Berger, Ariad's founder,chairman and CEO, added, "The lead molecules we havedeveloped for what we call our 'flagship project,' theallergy/asthma program, will probably go into animal studieslater this year."
He told BioWorld that the company has filed patentapplications covering protein-protein interactions, the targets,their structure, the classes of molecules that block theinteractions, and actual compounds that block mast-celldegranulation and activation in the allergic response.
Ariad's "key differentiation," Berger explained, "is that manygroups have looked at inhibiting receptor-ligand interactionson the outside of the cell. Our approach is to go into the cell andblock the first step of signal transduction." He pointed out thatthis approach "is completely independent of the allergen. If youtried to block the interaction of the allergen, say, to IgE, thiswould mean a different drug for each and every allergen. Butthey all signal through a single receptor, which in turn passesthe message on internally to a common pathway. What we areblocking is the first step of that internal common pathway."
To which Brugge added that the allergy program will serve asthe prototype for designing similar small-molecule inhibitors ofprotein-protein interactions inside the cell to prevent or treatother diseases.
"We won't need hospitalization to get treatment," she foresees.As putative examples, Brugge cited osteoporosis and"hyperproliferative disorders such as psoriasis and mammarycancer. It can also deal with autoimmune diseases generally, bydesigning an inhibitor of T-cell or B-cell activation. And shesummed up: "The basic science discoveries in this exciting newarea have identified very attractive targets for the nextgeneration of drugs."
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.