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Pepducin Symposium Explores a New Approach to GPCR Modulation Ann. N.Y. Acad. Sci. ISSN 0077-8923 ANNALS OF THE NEW YORK ACADEMY OF SCIENCES Insider access: pepducin symposium explores a new approach to GPCR modulation Jacquelyn Miller,1 Anika Agarwal,2 Lakshmi A. Devi,3 Kellen Fontanini,4 James A. Hamilton,4 Jean-Philippe Pin,5 Denis C. Shields,6 C. Arnold Spek,7 Thomas P.Sakmar,8 Athan Kuliopulos,2 and Stephen W. Hunt III9 1MacDougall Biomedical Communications, Wellesley, Massachusetts, USA; 2Tufts Medical Center, Boston, Massachusetts, USA; 3Mount Sinai School of Medicine, New York, New York, USA; 4Boston University School of Medicine, Boston, Massachusetts, USA; 5University of Montpellier, Montpellier, France; 6The University College of Dublin, Dublin, Ireland; 7University of Amsterdam, Amsterdam, the Netherlands; 8The Rockefeller University, New York, New York, USA; 9Ascent Therapeutics, Cambridge, Massachusetts, USA Address for correspondence: Stephen W. Hunt III, Ascent Therapeutics, 67 Rogers Street, Cambridge, MA 02142. [email protected] The inaugural Pepducin Science Symposium convened in Cambridge, Massachusetts on March 8–9, 2009 provided the opportunity for an international group of distinguished scientists to present and discuss research regarding G protein–coupled receptor-related research. G protein–coupled receptors (GPCRs) are, arguably, one of the most importantmoleculartargetsindrugdiscoveryandpharmaceuticaldevelopmenttoday.Thissuperfamilyofmembrane receptors is central to nearly every signaling pathway in the human body and has been the focus of intense research for decades. However, as scientists discover additional properties of GPCRs, it has become clear that much is yet to be understood about how these receptors function. Everyone agrees, however, that tremendous potential remains if specific GPCR signaling pathways can be modulated to correct pathological states. One exciting new approach to this challenge involves pepducins: novel, synthetic lipopeptide pharmacophores that modulate heptahelical GPCR activity from inside the cell membrane. Keywords: pepducins; G protein–coupled receptors; transmembrane signaling; meeting report On March 8–9, 2009, a group of scientists involved synaptic neurotransmission; targeted cell migration in pepducin research presented their latest findings in developmental pathways and inflammation; stem at the Pepducin Science Symposium in Cambridge, cell homing; hormone signaling systems; and other Massachusetts. This highly focused two-day event important mechanisms involving cell–cell commu- provided timely highlights to some of the most ex- nication all involve GPCR activation. Nearly one in citing areas in G protein–coupled receptor biology. three commercialized compounds are designed to The symposium was organized by Stephen Hunt modulate GPCR function, and the annual revenue III (Ascent Therapeutics), Athan Kuliopulos (Tufts from sales of these drugs makes up a significant Medical Center), and Thomas Sakmar (The Rocke- fraction of all pharmaceutical revenue. However, feller University). as scientists discover additional properties of this receptor superfamily, they also continue to realize how much is not yet understood about receptor Introduction and history of pepducins function. Everyone agrees, however, that tremen- G protein–coupled receptors (GPCRs) are, arguably, dous potential remains if specific GPCR signaling the most important molecular target class in drug pathways can be modulated to correct pathological discovery and pharmaceutical development today. states. The Pepducin Science Symposium success- GPCRs are membrane receptors that are central to fully stimulated discussion concerning pepducins just about every signaling pathway in the human and their potential applications in GPCR research body: visual, olfactory, and taste sensory systems; and GPCR-targeted drug discovery. Ann. N.Y. Acad. Sci. 1180 (2009) E1–E12 c 2009 New York Academy of Sciences. E1 Insider access Miller et al. Table 1. A brief history of GPCR research related to pepducins Opioid receptor heterodimers characterized 1999 Devi First GPCR (rhodopsin) crystal structure 2000 Palczewski GABA receptor heterodimers/allosterism elucidated 2001 Pin Pepducin agonist/antagonist activity demonstrated in vitro 2002 Kuliopulos First trials for antagonist pepducins in animals 2002 Kuliopulos Chemokine receptor pepducins developed 2005 Kaneider Pepducin inhibition activity in tumor models shown 2005 Agarwal Heterodimer-targeted pepducins developed 2006 Leger First trials for agonist pepducins in animals 2007 Kaneider Pepducin activity used to study sepsis and DIC 2007 Spek First bioinformatic-based pepducin-like molecules developed 2007 Shields Membrane flipping of pepducins demonstrated 2009 Hamilton The Pepducin Science Symposium was jointly meeting by summarizing key developments in the chaired by Athan Kuliopulos, Thomas P. Sakmar, field. and Stephen W. Hunt III. The symposium featured Pepducins were developed in the late 1990s many of the scientists who have contributed to the when scientists at the Tufts Medical Center literally growing body of knowledge surrounding pepducins turned the problem of GPCR-targeted drug discov- and GPCRs over the past dozen years and was ery inside-out—instead of looking at GPCRs from assembled to discuss the current state of pep- outside the cell, they began looking at ways to tar- ducin research (Table 1). Presenters traveled from get the receptors at the intracellular face, on the as far away as the Netherlands, France, and Ire- flip side of the cell membrane. As elaborated by Dr. land to share research on topics ranging from mem- Kuliopulos, “pepducins are designed to target re- brane biophysics and biochemistry to bioinformat- calcitrant GPCRs at the inside surface of the cell. ics and molecular oncology, each with a unique Because pepducins can penetrate the cell and can perspective on how pepducins might aid in on- either agonize or antagonize their targets, they are going efforts to understand and modulate GPCR a potent tool both for research and therapeutic ap- activity. Presentations highlighted new informa- plications. Pepducins can greatly increase both the tion around the mechanism of action of pepducins range of tractable targets and the specificity with and demonstrated ways in which these molecules which we can modulate their effect.” As originally are already creating some excitement in GPCR- published in the Proceedings of the National Academy related drug development. The meeting format of Sciences,1 pepducin lipopeptides can exhibit ago- encouraged an energetic discussion that touched nist or antagonist activity for their cognate receptor on many “hot-topic” GPCR questions, including (Fig. 1). The initial strategy was to synthesize a series dimerization, allosteric modulation, various strate- of third intracellular loop (i3) peptides attached to gies to achieve agonist and antagonist properties, an N-terminal lipid tag that would partition the pep- and the issue of GPCR deorphanization. Accord- tide into and across the lipid bilayer of whole cells. ing to Dr. Kuliopulos, the scientific founder of As- The N-terminal lipid would also serve to anchor the cent Therapeutics, of the greater than 700 GPCRs intracellular loop peptide to the lipid bilayer, in- encoded in the human genome, over 100 with creasing the effective concentration in the vicinity known or presumed therapeutic potential have of the GPCR target. Subsequent studies showed that not yet been successfully targeted, but these may certain pepducins based on the i1, i2, and i4 loops be amenable to pepducin technology. Dr. Kuliop- could also act as either agonists or antagonists of re- ulos, who has been involved in GPCR research ceptors, such as protease-activated receptors (PAR1, for nearly 15 years, is one of the pioneers in- PAR2, PAR4) and chemokine receptors (CXCR1, volved in the discovery of pepducins. He started the CXCR2, and CXCR4).2,3,4 E2 Ann. N.Y. Acad. Sci. 1180 (2009) E1–E12 c 2009 New York Academy of Sciences. Miller et al. Insider access Figure 1. Proposed mechanism of membrane flipping and interaction of pepducins with their cognate receptor on the inner leaflet of the lipid bilayer. Palmitoylated peptides derived from the 3rd (i3) intracellular loop of PAR1 act as either full agonists or antagonists of PAR1, depending on the sequence of the i3-peptide. The palmitate moiety (green) first partitions the lipopeptide into the outside surface of the cell membrane. The lipid tether then facilitates flipping of the pepducin across the lipid bilayer where it can interact with its cognate receptor and either block or stimulate signaling to associated G proteins. (Adapted from Covic et al.1). In addition to serving as useful tools to study re- A dynamic model for GPCR activation ceptor signaling and mechanisms in cell-based sys- • A recently elucidated model of GPCR activation tems, pepducins were shown to possess attractive shows dramatic conformational changes between drug-like characteristics that were deduced from active and inactive GPCR states at the intracellular pharmacokinetic, pharmacodynamic, biodistribu- junction. tion, and other preclinical studies in mice, guinea • Findings help explain the mechanism of action pigs, and baboons. The first pepducin studies in for pepducin agonism or antagonism of GPCR mice, published in Nature Medicine,5 showed that receptors. a pepducin based on PAR4 (a thrombin receptor expressed in platelets and other cells), P4pal-10, In their 2008 Nature paper, “Crystal structure of prevents activation of platelets
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