MIAMI BEACH, Fla. -- One of mankind's most persistentmaladies -- the common cold -- is caused by his smallestenemy, the human rhinovirus.
Structural biologist Michael G. Rossmann of Purdue Universityin West Lafayette, Ind., told attendees at the 1993Biotechnology Winter Symposium here last week how he andhis research team at Purdue University explored the molecularand atomic architecture of rhinovirus in order to develop anti-viral drugs against the common cold. Rossmann presented thisyear's Feodor Lynen Lecture, which honors Nobelist Lynen, aGerman biochemist and visiting professor at the University ofMiami, who died in 1979.
In 1985, Rossmann reported mapping in atomic detail thethree-dimensional structure of the common cold virus by X-raycrystallography. In so doing, his group was the first to solve thestructure of any animal virus.
He has since collaborated with the Sterling-Winthrop ResearchInstitute in Rensselaer, N.Y., which is tailor-making compoundsthat can put spokes in the virus' wheel.
Actually, the rhinovirus is shaped more like a ball than awheel; its spherical surface consists of 20 seamless trianglesthat constitute an icosahedral capsid.
This protein shell envelops a core of RNA. Picture a soccer ball(also constructed of geometric patches) some 10 inches indiameter shrunk to 300 Angstroms -- the external diameter ofa rhinovirus particle. (Put another way, it would take 300million of those virions to span a millimeter.) They solved thestructure to 3 angstroms.
This viral geometry begins to explain Rossmann's strategy inseeking a pharmacological chink in the rhinoviral armor.Around the points where each set of five triangles interface, hedraws a thick, wide circle, defining a cleft or canyon in itssurface. It leads to his "canyon hypothesis" as to how the virusevades the body's immune defenses. The canyons' surfacegrooves, about 12 angstroms deep by 12 to 15 wide, harbor thesites where the rhinovirus receptors grapple to various targetcells in the upper respiratory tract ("rhino" comes from "nose"in Greek). The sites are too narrow for immune-defenseantibodies to enter.
The cut-out in this sinister attack is a ligand called ICAM-1, forinter-cellular adhesion molecule. "ICAM binds the middle of thetriangle," Rossmann explained, "and fits beautifully in thecanyon, with their individual atoms actually in contact."
He added, "It's the first time anybody has got atomic resolutionstructure of a virus-receptor interaction."
In screening what Rossmann describes as "a whole slew" ofnovel potentially anti-viral agents, Sterling-Winthrop medicinalbiochemists have come up with several so-called "WIN" (forWinthrop) compounds that snuggle into a cave-like pocketbeneath the canyon and raise its floor level to squeeze out theICAM-1 grappling hooks. This prevents the viral coat frombreaking open to release its infectious RNA.
Sterling-Winthrop microbiologist Mark McKinlay, who directsthe joint research effort, has said, "We knew the compoundsblocked the viral uncoating process, but not how or why.Rossmann's research has brought us to a unique position indrug discovery by showing how compounds interact at themolecular level."
Sterling is developing its drugs for oral delivery, Rossmannsaid. He described the clinical trial of a similar Belgiancompound designed as a nasal spray. Twenty-five volunteersgot daily doses of the spray; another 25 controls inhaled aplacebo. Their daily output of nasal discharge was weighed toquantify the severity and duration of their colds. At the end ofa week, the controls were producing an average 3 grams; theactive-drug cohort only 0.5 grams.
Rossmann explained why, unlike polio, a vaccine against thecommon cold is impractical. "The polio virus," he told hisaudience at the symposium, "has only three known serotypes(antigen patterns), while rhinovirus has 102 known strains sofar, and still counting."
In introducing Rossmann, Gary Temple, research vice-presidentof GIBCO-BRL/Life Technologies Inc. (which sponsors theannual Lynen Lectures), hailed his feat of rhinovirus structuralmapping as "a tour de force in modern crystallography ...permitting major advances in the rational design of anti-viraldrugs."
And Sterling spokesman Terry G. Kelley told BioWorld: "Ourcollaboration with Rossmann has been very beneficial indirecting our drug-discovery efforts." His company is activelypursuing its anti-viral program, Kelley added, but "does not atpresent have any compounds in preclinical development."
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.