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Separation of On-Target Efficacy from Adverse Effects Through Rational Design of a Bitopic Adenosine Receptor Agonist

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Separation of On-Target Efficacy from Adverse Effects Through Rational Design of a Bitopic Adenosine Receptor Agonist Separation of on-target efficacy from adverse effects through rational design of a bitopic adenosine receptor agonist Celine Valanta,1, Lauren T. Maya,1, Luigi Aureliob, Chung Hui Chuoa, Paul J. Whitea, Jo-Anne Baltosa, Patrick M. Sextona, Peter J. Scammellsb,2, and Arthur Christopoulosa,2 aDrug Discovery Biology and Department of Pharmacology and bMedicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia Edited* by Robert J. Lefkowitz, Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC, and approved February 10, 2014 (received for review November 6, 2013) The concepts of allosteric modulation and biased agonism are rev- The adenosine receptor (AR) family is an important class of olutionizing modern approaches to drug discovery, particularly in physiologically and therapeutically relevant GPCRs that can ben- the field of G protein-coupled receptors (GPCRs). Both phenomena efit substantially from more selective drug targeting. Although all exploit topographically distinct binding sites to promote unique four AR subtypes are expressed in the mammalian heart (11, 12), GPCR conformations that can lead to different patterns of cellular the well-known protective effects of adenosine in this tissue are responsiveness. The adenosine A1 GPCR (A1AR) is a major thera- predominantly mediated by the adenosine A receptor (A AR) peutic target for cardioprotection, but current agents acting on 1 1 subtype, especially under conditions of ischemia and reperfusion the receptor are clinically limited for this indication because of on- – target bradycardia as a serious adverse effect. In the current study, injury (13 17). Unfortunately, the transition of A1AR agonists into the clinic has been severely hindered because of high doses causing we have rationally designed a novel A1AR ligand (VCP746)—ahybrid molecule comprising adenosine linked to a positive allosteric mod- on-target bradycardia, atrioventricular block, and hypotension (13, ulator—specifically to engender biased signaling at the A1AR. We 18). As a consequence, clinical trials of AR agonists have had validate that the interaction of VCP746 with the A1AR is consistent limited success because of the suboptimal dose of agonist that can with a bitopic mode of receptor engagement (i.e., concomitant as- be used (19–22). It is possible that this problem may be overcome sociation with orthosteric and allosteric sites) and that the com- through the exploitation of biased agonism at the A1AR. pound displays biased agonism relative to prototypical A1AR Although no study has identified biased orthosteric A1AR ligands. Importantly, we also show that the unique pharmacology ligands, we recently showed that the 2-amino-3-benzoylthiophene of VCP746 is (patho)physiologically relevant, because the com- allosteric modulator (VCP171) could promote biased signaling in pound protects against ischemic insult in native A1AR-expressing the activity of the prototypical orthosteric agonist, R(-)N6- cardiomyoblasts and cardiomyocytes but does not affect rat atrial (2-phenylisopropyl) adenosine (R-PIA) (23). Thus, we hypothe- heart rate. Thus, this study provides proof of concept that bitopic sized that the rational design of a bitopic ligand (i.e., a class of ligands can be designed as biased agonists to promote on-target efficacy without on-target side effects. hybrid molecule containing both orthosteric and allosteric phar- macophores) (24–26) may be able to achieve high efficacy and bi- ased agonism at the A AR in a single molecule. Herein, we report protein-coupled receptors (GPCRs) are the largest family 1 G of cell surface proteins and tractable drug targets (1, 2). Unfortunately, there remains a high attrition rate associated with Significance traditional GPCR-based drug discovery that, in part, reflects an emphasis on the endogenous agonist binding (orthosteric) site as The adenosine A1 receptor (A1AR) is an important target for the predominant means of achieving selective GPCR drug tar- cardioprotection, but current A1AR drugs are limited for this geting (3). Over the last decade, substantial breakthroughs have indication because of the occurrence of bradycardia as a major adverse effect mediated by the same receptor. To address this occurred in the exploitation of topographically distinct GPCR problem, we designed a ligand that simultaneously bridges allosteric sites as a means for attaining greater selectivity, espe- two different sites on the A AR; the hypothesis is that this cially in those instances where there is high sequence similarity in 1 – bitopic mode would result in unique receptor conformations the orthosteric site across GPCR subtypes (4 6). However, there that will signal to desirable pathways while sparing those path- are increasing examples where both the therapeutic effect and ways mediating undesirable effects. This mechanism was vali- adverse effects are mediated by the same GPCR target (7). In dated in native rodent cells and isolated rat atria, providing proof these situations, the desired selectivity needs to be attained at of concept that the design of bitopic ligands may be a path for- the level of the intracellular signaling pathways linked to a given ward to separating beneficial from harmful effects mediated by receptor subtype. thesamedrugtarget. GPCRs are highly dynamic proteins, fluctuating between dif- ferent conformations; these conformations can be linked to dif- Author contributions: C.V., L.T.M., L.A., P.J.W., P.M.S., P.J.S., and A.C. designed research; ferent cellular outcomes (8). Thus, chemically distinct ligands, C.V., L.T.M., L.A., C.H.C., P.J.W., and J.-A.B. performed research; L.A. contributed new reagents/analytic tools; C.V., L.T.M., C.H.C., P.J.W., J.-A.B., and A.C. analyzed data; and interacting with either orthosteric or allosteric sites, have the po- C.V., L.T.M., P.M.S., P.J.S., and A.C. wrote the paper. tential to stabilize different interaction networks within a GPCR to The authors declare no conflict of interest. promote a subset of signaling pathways linked to the receptor at *This Direct Submission article had a prearranged editor. the expense of others. This phenomenon has been termed biased 1C.V. and L.T.M. contributed equally to this work. agonism (7, 9, 10). The overall promise of biased agonism is the 2To whom correspondence may be addressed. E-mail: [email protected] or ability to design GPCR ligands that selectively engage therapeu- [email protected]. tically relevant signaling pathways while sparing pathways that This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. contribute to undesirable side effects mediated by the same target. 1073/pnas.1320962111/-/DCSupplemental. 4614–4619 | PNAS | March 25, 2014 | vol. 111 | no. 12 www.pnas.org/cgi/doi/10.1073/pnas.1320962111 Downloaded by guest on September 28, 2021 proof of concept that it is possible to use this approach as a using only the allosteric site and thus, allow an allosteric in- means to dissociate on-target efficacy from on-target side effects. teraction between the two molecules to occur (24–26, 30). If the allosteric moiety displays agonism, then the additional potential Results exists for a noncompetitive interaction when the ligands are Rationale for Design and Synthesis of Hybrid Orthosteric/Allosteric interacting allosterically. As shown in Fig. S2, this situation is in- Ligands of the A1AR. Fig. 1 summarizes the chemical biology deed the case when VCP171 (allosteric agonist) is tested against 8- framework underpinning the generation of hybrid orthosteric/ cyclopentyl-1,3-dipropylxanthine (DPCPX; orthosteric antagonist) allosteric ligands for the current study. We chose to link the in an assay of A1AR-mediated ERK1/2 phosphorylation, whereas endogenous agonist, adenosine, to the allosteric modulator, simple competition is observedwhenanorthostericagonist VCP171 (Fig. 1A and Fig. S1), with the hypothesis being that the (R-PIA) is used. Thus, it may be predicted that a bitopic ligand adenosine moiety would confer high efficacy to the hybrids, retaining these features would display a mixed mode of competi- whereas the VCP171 moiety would induce biased signaling (23). tive (at lower concentrations of antagonist) and noncompetitive Although the location of the allosteric site on the A1AR has not antagonism (at higher concentrations of antagonist). If biased been definitively determined, it is thought to comprise residues agonism is attained, Fig. 1C illustrates an idealized pathophysio- that are more extracellular to the orthosteric site (27–29). As- logically relevant outcome for cardiac A1ARs, where on-target suming that the hybrid molecule binds concomitantly to both cytoprotection is attained in the absence of on-target bradycardia. sites in this topography, Fig. 1B illustrates schematically the simplest expectations arising from such a bitopic mode of ori- Hydrid Orthosteric/Allosteric Ligands Are Potent Agonists of the A1AR. entation with two assumptions. (i) A bitopic mode of engagement It is known that the introduction of bulky substituents at the N6 would represent the higher-affinity interaction and be largely in- position of adenosine is often well-tolerated (31, 32). The in- distinguishable from a reversible competitive interaction, because troduction of bulky substituents at the four and five positions of the orthosteric site is engaged (in addition to the allosteric site). the thiophene ring of 2-amino-3-benzoylthiophene modulators
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