Download Lefkowitz is working on a new kind of heart failure drug “combining

The 2009 BBVA Foundation Frontiers of Knowledge Award laureate in
Biomedicine believes the approach he is developing could be applied to
dozens of pathological conditions
Lefkowitz is working on a new kind of heart
failure drug “combining greater efficacy
with fewer side effects”

His current research builds on his discoveries about the role of beta-arrestins
and is geared to the treatment of acute heart failure

These insights also open up exciting new avenues for the treatment of pain

Robert J. Lefkowitz is in Madrid to collect the BBVA Foundation Frontiers of
Knowledge Award in Biomedicine for identifying the receptors targeted by
half of today’s drugs
Madrid, June 23, 2010.- Robert J. Lefkowitz, 2009 BBVA Foundation Frontiers of
Knowledge Award laureate in Biomedicine, is working on an agent for the treatment of
acute heart failure, whose mechanism “opens the possibility of developing an entirely
new class of therapeutics”.
The drug – in phase I clinical trials since April last being assessed for safety and
absorption in human subjects – is a product of Lefkowitz’s latest research, building on
the insight that earned him the 2009 BBVA Foundation Frontiers of Knowledge Award in
Biomedicine: the identification of the receptors targeted by half of today’s prescription
drugs.
Twenty-five years ago, Robert J. Lefkowitz successfully cloned the gene for the betaadrenergic receptor, which regulates the flow of adrenaline to the heart. This was the
first proof that receptors existed as specific protein structures; a thesis that was
controversial at the time. “Receptors are molecules on the surface of or within all cells
of the body which bind to or interact with all manner of hormones, drugs and
neurotransmitters. They are able to recognize these drugs and hormones based on
some complementarity in their molecular structures, much as a key (the drug) fits into a
lock (the receptor).
But there was more to come. Lefkowitz found that the seven-segment structure of
adrenergic receptors occurred in around a thousand others. Nowadays this vast
receptor family is known to regulate “virtually every known physiological process”,
Lefkowitz explains. They are the “locks” permitting entry to numerous drug types like the
antihistamines, serotonins and opiates vital in the fight against allergies, depression and
pain.
New dual-purpose medicines
“For many years it was thought that the sole way in which seven-transmembranespanning receptors worked was by stimulating a type of protein called a G protein.
Once they are stimulated, however”, Lefkowitz points out, “they can also be turned off
by another type of protein called beta-arrestins.” It is very likely these arrestins, with their
power to desensitize seven-transmembrane-spanning receptors, which explain the
diminished efficacy over time of epinephrine (synthetic adrenaline) or morphine.
“Recently we discovered that the beta-arrestins can also transmit signals from the
receptors to biochemical pathways inside the cell. Moreover, we found that it is
possible to develop drugs which can block signaling through the G protein mechanism
while simultaneously stimulating activities through the beta-arrestin mechanism or vice
versa. In such cases, the drug would actually be an antagonist (blocker) of certain
signals and, at the same time, an agonist (stimulator) of others.”
“This new understanding has opened the possibility of developing an entirely new class
of therapeutics”, Lefkowitz continues. “All previously developed drugs which act
through seven-transmembrane-spanning receptors either stimulate or block all receptor
activities. However, sometimes the desired receptor mediated effect is mediated
through either G protein or beta-arrestins and unwanted side effects are mediated
through the other mechanism.
Drugs which distinguish these signaling mechanisms have the potential to be much
more specific, and to have fewer side effects.”
It is precisely this kind of agent that Trevena, the biotech company which Lefkowitz
co-founded some years back, has tested in animals and is now testing in humans as
a treatment for acute heart disease. “The new drug acts by blocking the angiotensin
receptor, as do other more traditional medicines. Unlike them, however, it also
stimulates beta-arrestin, which may have desirable effects such as increasing the
strength of heart beats and preventing cellular death. This drug is in early phase
clinical trials but the approach is entirely general and could potentially be used on
many different seven-transmembrane-spanning receptors.”
Another possible application, Lefkowitz remarks, is in the treatment of pain. “The pain
relieving effects of opiates appear to be mediated through G protein signaling but
the side effects of respiratory depression and tolerance, leading to the requirement
of ever greater doses, are mediated through beta arrestins. In this case, a “G protein
biased” agonist drug for the opiate receptor could be more specific and have fewer
side effects.”
Lefkowitz is confident that the development of this technology – known by the name
of biased ligands – “opens the possibility of an entirely new therapeutic approach
which can, at least in theory, be applied to any seven-transmembrane-spanning
receptor and to potentially dozens of pathological conditions. The reality of this
therapeutic vision, however, remains to be tested in the clinic and validated, as with
all scientific ideas.”
AWARD WINNERS
The BBVA Foundation Frontiers of Knowledge Awards honor world-class research and
artistic creation across eight prize categories. Their uniqueness lies in their close
alignment with the scientific, technological, social and economic challenges of the
present century. Thus categories are reserved for Development Cooperation,
Information and Communication Technologies, Ecology and Conservation Biology,
and Climate Change, alongside the awards going to outstanding contributions in
Economics, Finance and Management, Basic Sciences, Biomedicine and
Contemporary Music.
The winners in this second edition of the BBVA Foundation Frontiers of Knowledge
Awards are:
Richard N. Zare, Marguerite Blake Wilbur Professor in Natural Sciences at Stanford
University (United States), and Michael E. Fisher, Distinguished University Professor and
Regents Professor at the University of Maryland (United States), share the BBVA
Foundation Frontiers of Knowledge Award in the Basic Sciences category.
Robert J. Lefkowitz, professor in the Department of Medicine at Duke University
(United States), obtains the BBVA Foundation Frontiers of Knowledge Award in the
Biomedicine category.
Peter B. Reich, professor at the University of Minnesota (United States), obtains the
BBVA Foundation Frontiers of Knowledge Award in the Ecology and Conservation
Biology category.
Thomas Kailath, Hitachi America Professor of Engineering, Emeritus, at Stanford
University (United States), obtains the BBVA Foundation Frontiers of Knowledge Award
in the Information and Communication Technologies category.
Andreu Mas-Colell, professor at Pompeu Fabra University, and Hugo Sonnenschein,
professor and President Emeritus at Chicago University, obtain the BBVA Foundation
Frontiers of Knowledge Award in the Economics, Finance and Management
category.
Cristóbal Halffter, Spanish composer and conductor, obtains the BBVA Foundation
Frontiers of Knowledge Award in the Contemporary Music category.
Klaus Hasselmann, Emeritus Director of the Max Planck Institute for Meteorology
(Hamburg, Germany), obtains the BBVA Foundation Frontiers of Knowledge Award in
the Climate Change category.
Development Research Institute (DRI) at New York University (United States) obtains
the BBVA Foundation Frontiers of Knowledge Award in the Development
Cooperation category. Collecting the award will be its co-directors, New York
University economics professors William Easterly and Yaw Nyarko.
The winners in the first edition of the BBVA Foundation Frontiers of Knowledge Awards
were:
Ignacio Cirac, head of the Theory Division at the Max Planck Institute of Quantum
Optics (Garching, Germany), and Peter Zoller, professor in the University of Innsbruck
(Austria), obtained the BBVA Foundation Frontiers of Knowledge Award in the Basic
Sciences category.
Joan Massagué, chairman of the Cancer Biology and Genetics Program at the
Sloan-Kettering Institute (New York, United States), obtained the BBVA Foundation
Frontiers of Knowledge Award in the Biomedicine category.
Thomas E. Lovejoy and William F. Laurance, biologists in the Smithsonian Institution
(United States), shared the BBVA Foundation Frontiers of Knowledge Award in the
Ecology and Conservation Biology category.
Jacob Ziv, professor at the Technion in Haifa (Israel), obtained the BBVA Foundation
Frontiers of Knowledge Award in the Information and Communication Technologies
category.
Jean Tirole, director of the Jean-Jacques Laffont Foundation at the Toulouse School
of Economics and scientific director of the Industrial Economics Institute of the same
French city, obtained the BBVA Foundation Frontiers of Knowledge Award in the
Economics, Finance and Management category.
Steven Holl, architect and professor in the Graduate School of Architecture at
Columbia University (United States), obtained the BBVA Foundation Frontiers of
Knowledge Award in the Arts category.
Wallace S. Broecker, professor in the Earth and Environmental Sciences Department
at Columbia University (New York, United States) and coiner of the term “global
warming”, obtained the BBVA Foundation Frontiers of Knowledge Award in the
Climate Change category.
Abdul Latif Jameel Poverty Action Lab (J-PAL) of Massachusetts Institute of
Technology (MIT), obtained the BBVA Foundation Frontiers of Knowledge Award in
the Development Cooperation category. The award was collected on J-PAL’s
behalf by its co-director, French economist Esther Duflo.
For further information, contact the BBVA Foundation Communication Department
(+34 91 374 52 10 or [email protected]) or see our website (www.fbbva.es)