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 upexciting 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 andabsorption 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 beta-adrenergic 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 familyis 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 opiatesvital 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-transmembrane-spanning 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 humansas 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 thefirst 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.

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