DOCSLIB.ORG

Oasis Kuliopulos V2

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Oasis Kuliopulos V2 Our experience with NIH/SMARTT resources to bring PepducinsTM from the bench-into-the-clinic Athan Kuliopulos, MD PhD, CEO, Oasis Pharmaceuticals 19th Annual HHS SBIR/STTR Conference Milwaukee, WI ! November 7, 2017 Overview # $%&'()*(+,-./%0)*(12,34.5'/.06)7,859:,34.,/5.;)<*(*)'<,73'+. *(39,)<*(*)'<,35*'<7,=*34,>?@,'(%,A2$B11,70//953 # C(35./5.(.05*'<,D')E+590(% # CF/.5*.().,=*34,-G;!"HI,?>JK,-4'7.,!,'(%,-4'7.,",35*'<7 # LM$ " The Company 1. Overview and background of Oasis Pharmaceuticals N Oasis Pharmaceuticals !"##"$% &&&&&'()(*$+"%,&+(+-./"%012#(-&34(52+(.6/#&7$5&34(&35(238(%3&$7 #()(5(&915$6/:"%;28823$5<&2%-&=>&-"#(2#(# # ?-,895,-$B",<*/9/./6%.7,P<.%,=*34,/5*95*3Q,%'3.,98,"R!S # 145..,)<*(*)'<,)'(%*%'3.7,4'&.,T..(,3.73.%,*(,'(*:'<7,895,.U)')Q,'(%,7'8.3Q *()<0%*(+,?>J;.('T<*(+,VW-,730%*.7 # -4'7.,!,)<*(*)'<,35*'<,*(,>@XY>$A@,9(,7)4.%0<.,895,"R!H # A.(*95,<.'%.574*/,3.':,=*34,%../,.F/.567.,*(,/5.;)<*(*)'<,'(%,)<*(*)'<,%50+ %.&.<9/:.(3 # A/*(;9Z,859:,10[7,2.%*)'<,\.(3.5,=*34,)9(6(0*(+,)9<<'T95'69(,=*34 ')'%.:*),*(&.76+'3957 O Pepducin Pipeline H@IF -5.)<*(*)'< ?>J -4,! -4," -4,N !"#$%&'()"*+,*+( J$%2*/$4$*"/&K3(23$4(+266#&LJ@KMN&?@0FGB" O-"$+234"/&H.*8$%25<&E"15$#"#&LOHEN&?@0FGB/ D"-%(<&E"15$#"#&?@0FGB" 2;%6"'()+$: -."/(01234(5%6"',78 H@IV 59$%:#%*"* ?@0ABC H@IA&05<=*(>+?"',7(@+/;+$8 59$%:#%*"* &&&&&&&&&&&&&&&&&&&&&&&&&&&=*"%"/2*R5"2*#S,$)&&&&J=RCFBTACCCU&&J=RCFBTACCC S HP0AFQ&@/.3(&/$5$%25<&"%3(5)(%6$%# Oasis Team Athan Kuliopulos, MD PhD, CEO • Inventor of Pepducin™ technology • Founder, CEO of Oasis Pharmaceuticals, LLC, 2013-present • Founder, CSO of Ascent Therapeutics, 2007-2010 • Raised $21M (A) from Novartis Option fund, HCV, TVM, plus additional funding ($10M) and partnerships with Novartis, J&J, and other Pharma • PI of NIH/NHLBI P50 to develop a PAR1 pepducin PZ-128 (currently enrolling PCI patients in a multi-center Phase 2 study) Lidija Covic, PhD, CSO • Co-Inventor of Pepducin™ technology • Founder, CSO of Oasis Pharmaceuticals, LLC, 2013-present • Founded Ascent/Anchor: SAB Member John Amedio, PhD, VP Chemistry and Manufacturing • CMC for lipopeptide therapeutics including PZ-128 • VP, Manufacturing and Chemistry, Seaside Therapeutics, Ziopharm Richard Looby, Director of Peptide Chemistry • Expert in pepducin design and synthesis Dana Minnick, PhD Regulatory Toxicology, IND-enabling studies, FDA Interactions Clinical Team: NASH CRN-Dr. Manal Abdelmalek, MD, Hepatologist, Duke Medical Center IPF-Dr. Steven Nathans, MD, Chief Pulmonary Medicine, Inova, VA AD-Dr. Alice Gottlieb, MD, Dermatologist-in-Chief, Tufts University School of Medicine 6 Pepducin technology 2.PAR2-a difficult-to drug receptor: Solution: Pepducin technologyTM ] Protease-Activated Receptor-2 (PAR2) J*U)0<3,39,')).77,12,%9:'*(,)95.,^<*+'(%_,7*3.7,'(%, Xa/TrypsinD<9)E,/593.'7.;')6&'3.%,5.)./395 Synthetic SKGR Ligand N 46 LDPR-SFLLSKGR Ligand R N OR LBS-1 LBS-1 Ligand LBS-2 N 37 LBS-2 TM3 TM6 ON TM3 OFF TM6 G!"# + G! + "# GDP GTP PepducinTM Technology Pepducin Lipopeptide structure: GPCR 1. Synthetic Peptide • 7-19 amino acid fragment of GPCR intracellular loop • Nature-engineered specificity 2. Hydrophobic moiety • Cell-penetrating / membrane tethering lipid (e.g., palmitate) 3. Screened PAR2-derived pepducins • Identified PZ-235 Sevigny et al PNAS (2011) 108:8491-6 ` PAR2 Antagonist: Rational Design of PZ-235 • Based on the PAR2 receptor structural model • Pharmacologic data identified key residues (red and blue) important in eliminating PAR2 receptor constitutive (ligand independent) activity -$B",/./%0)*(-$B", -G;"NS -$B" -$B" !R PD-PK Pepducins are stable and have long half-lives in plasma t1/2~4-6h !! W"$-"#35"1.6$%&$7&AV=0*21(**(-&&HP0FGB Into fibrosis-prone Organs, e.g. lung, liver, kidney PAR2 pepducin has long tissue half-life and is widely distributed !" Opportunity: Large Unmet Medical Need in IPF • Two approved oral drugs sold at high cost Nintedanib (Ofev) Boehringer Ingelheim Pirfenidone (Esbriet) Roche • Limited benefit with high potential side effects • IPF market to surpass $1 Billion in 2017 H@IF&"#&4",4*<&.+5(,.*23(-&"%&*.%,&6##.( 75$8&OHE&#.1X(/3#&2%-&"#&/$55(*23(-&Y"34 Y$5#(&/*"%"/2*&$.3/$8( 13 Summary of effort in IPF • Product: OA-235c Lead Clinical Candidate Idiopathic Pulmonary Fibrosis (IPF) • Identified OA-235c as a protease-resistant lipopeptide • SubQ injectable developed for systemic administration; aerosol delivery is a long-term goal • PK conducted in mouse and dog showing high AUC and sustained drug levels in plasma • Milestones completed in partnership with NHLBI SMARTT program • Dose-escalation dog safety study • CV (GLP) dog pharmacology-tox study • Genotox panel (GLP) • AMES • Mouse micronucleus study (up to 200 mg/kg) • Chromosomal abnormality (Clastogenic) • Remaining IND-enabling studies - funding pending !O Summary of efforts in NASH • Product: OA-235i Lead Clinical Candidate • Nonalcoholic steatohepatitis (NASH) • Currently no approved treatments for NASH except for life style change and antioxidants • Major milestones accomplished: • Identified OA-235i with 25-fold higher potency • SubQ injectable developed for daily-to-weekly administration • PK conducted in mouse, rat, dog showing high AUC and sustained drug levels in target tissue-namely liver • 28 day rat and 7 day dog completed showing high therapeutic safety margin • Pre-IND meeting held with FDA and identified regulatory pathway through IND and phase 1 trial • Additional indication is kidney fibrosis • Expected IND in mid-2018 for NASH (funding secured) • First-in-human trial in NHV and NASH subjects in late-2018 (funding secured): single and multi-dose ascending study to be done at Duke Medical Center !S Future earning Projections for entire market !a Competition in NASH $GILD(ACC) $BMS(FGF-21) Majority of experimental Limited number of anti-fibrotic agents agents target steatosis !] Z#321*"#4(-&I$*(&$7&H@IF&"%&[")(5&E"15$#"#&2%-&O%;28826$% Normal NASH Fibrotic/Cirrhotic Liver Coagulation proteases Liver Inflammatory proteases protease Activated cleavage PAR2 PAR2 TF in Cirrhotic liver Stellate Cell Proliferative Myofibroblast LX-2 Proliferation/ERK signaling PAR2-ab Extracellular matrix deposition collagen 2o-ab Production of inflammatory Cytokines !H TNF!, IL-6, MCP-1, IL-8 @%60J@E['&2/6)"3<&"%&#()(5(&G&Y((\&!='&8$-(* !` @%60915$6/&2,(%3&"%&Q&Y((\&==*V&8$-(* '(*2<(-&R5(238(%3&Y"34&HP0FGB&K.++5(##(#&&[")(5&E"15$#"# "R W5$2-&!?@&7$5&H@IF&H(+-./"%&3$&K.++5(##&J@KM >%?+(%A(,'&%/(0>%28B @&H@IF&+(+-./"%&Y"**&1(&/*"%"/2**<&-"](5(%623(-&1<&2/6%,&2#&2%^ CD(,/&3E#$%&'(,F+/;B(4'<3,95,5.&.57.,PT596),*(%*).7 GD(,/&3"/H,::,;%$I(,F+/; 4D(A,JI(7"K+$3*<66$+**"K+(,F+/;B(D<9)E,95,5.&.57.,/59+5.77*9(,98,8'bQ,<*&.5K,4./'39).<<0<'5 *(c05Q,d$W1K,$A1eK,35*+<Q).5*%.7K,<9=.5,@T$!),*(,%*'T.6)7 L:67%I,$%#<*;(M9,$:,'%?I/,:"'(:,$.+$*(34'3,)955.<'3.,=*34,-$B",')6&*3QK,.f+f,@T$!)K $W1K,g$\7;T'7.%,'77'Q,98,:9(9)Q3.7 M9,*+(NNB(M$%%A3%A3@%/'+6;(0M%@8(A30%Q,*(,aR,/'6.(37,d!,:9(34,;,a,:9(34,903)9:.7eK,<*&.5 .<'739+5'/4QK,2B,<*&.5,73.'397*7,d)'(,'))05'3.<Q,:.'705.,hSi,)4'(+.e "! Timeline for Completion of IND/Phase 1 for OA-235i in NASH # J@KM0H5(OJ'&8((6%,&Y"34&E'@&Y2#&4(*-&_G&FCATS&@%&2,5((8(%3&Y2# 5(2/4(-&$%&34(&+5(/*"%"/2*&2%-&/*"%"/2*&-()(*$+8(%3&+*2%#&7$5&34(&()2*.26$% $7&?@0FGB"&2#&2&35(238(%3&$7&J@KM&+26(%3#&"%&4.82%&/*"%"/2*&35"2*# # OJ'&3$&1(&/$8+*(3(-&1<&72**&$7&FCAQ # H42#(&A&K@'&2%-&!@'&"%&GV&JM>#&2%-&J@KM&#.1X(/3# 3$&1(&"%"623(-&"%&*23(&_V&FCAQ Q3 Phase 1 2016 Phase 1 GLP tox/safety IND complete FDA preIND initiation meeting completion FPFV Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 2017 2018 2019 "" Utilizing the NHLBI SMARTT Program 3. Developing a PAR1 pepducin from bench-to-Phase 2 clinical trials and beyond "N @/.3(&8<$/25-"2*&"%725/6$% • Interruption of oxygen supply to the heart • Causes death of the heart muscle • A leading cause of death in both men and women • Patients with ACS treated with PCI/stent and anti-platelet agents QTV CVD deaths vs. cancer deaths by age (United States) NHLBI Increased bleeding risk ?)(52**&`$2*#&$7&34(&H5$X(/3 ! )+K+7%6(,/("/;$,K+/%<*(,/&67,;+7+;(,F+/;(A%$(2@-(6,&+/;*(</?+$F%"/F(M@N ! )<,7(:%?+(%A(,'&%/(0>%28B CD(!,*;(%/*+;B(I2+"-&+5$3(/6$%&23&34(&#3253&$7&H=O&+5$/(-.5( GD(O+K+$*"#7+(:+'9,/"*:(%A(,'&%/^&H5$3(/6$%&-.5"%,&H=O&+5$/(-.5(&Y"34&3(58"%2* 42*70*"7(&aFV&4S ! @%/?<';(NP)3+/,#7"/F(+Q','IR(*,A+;I(,/?(;%S"'%7%FI(*;<?"+*("/(G(*6+'"+* ! M9,*+(NB(-,A+;IR(;%7+$,#"7";IR(?%*+($,/F"/F("/(4G(*<#T+';*(U";9(@2)V$"*.(A,';%$* MW('%$$+7,;+*(U";9(,/&367,;+7+;(+X+';* ! M9,*+(NNB(CYY(M,&+/;*(</?+$F%"/F(M@N (><7&'+/;+$R(M7,'+#%3'%/;$%77+?()%<#7+(Z7"/?+?R()%*+3+*',7,&%/ (-,A+;IR(LQ','I ! M9,*+(NNNB([4\(M,&+/;*(U";9(P-5L>NV2@-(%$(*;,#7+(@2)(06+/?"/F(A</?"/F8 ]<+*&%/B(@,/(;9"*(#+(,''%:67"*9+?(;9$%<F9(PN^(!</?"/F(>+'9,/"*:*_ Center of Hemostasis and Thrombosis Research at Tufts and NHLBI / RTI / SRI SMARTT 36 Opened IND "a Protease-Activated Receptor-1 (PAR1) Thrombin TR16 Synthetic Ligand N 26 LDPR Ligand 26 LDPRLDPR Ligand OR LBS-1 LBS-1 H Ligand i LBS-2 r N 42 LBS-2 TM3 TM6 ON TM3 OFF TM6 G!"# + G! + "# GDP GTP =$**2,(%&5(*(2#(# #.572/(&1$.%-&!!H0A& 75$8&+*23(*(3# !!HA&@/6)23(#&H@IA MMP1 cleaves PAR1 extracellular domain at a novel site R Trivedi et al.
Load more

Recommended publications
  • Recent Advances in Drug Discovery of GPCR Allosteric Modulators
    Recent Advances in Drug Discovery of GPCR Allosteric Modulators ADDEX Pharma S.A., Head of Core Chemistry Chemin Des Aulx 12, 1228 Plan-les-Ouates, Geneva, Switzerland Jean-Philippe Rocher, PhD results in a number of differentiating factors. In fact, most Introduction allosteric modulators have little or no effect on receptor function until the active site is bound by an orthosteric The importance of the allosteric regulation of cellular ligand. Allosteric modulators therefore have multiple functions has been known for decades and even the word potential advantages compared to small molecule and “allosterome,” which describes the endogenous alloste- biologic orthosteric drugs. In particular, they offer new ric regulator molecules of a cell, has been proposed 1. chemistry possibilities allowing access to well known tar- Although best described as modulators of enzymes, gets that have been considered intractable to historical advances in molecular biology and robotic HTS technolo- small molecule approaches. For example, allosteric mod- gies recently allowed the discovery of small molecule allo- ulators may soon be developed for targets which hereto- steric modulators of various biological systems, including fore have been only successfully targeted with proteins GPCR and non-GPCR targets. Today, allosteric modula- and peptides. In other words, allosteric drugs with all the tors appear to be an emerging class of orally available advantages of small molecules － brain penetration, eas- therapeutic agents that can offer a competitive advantage ier manufacturing, distribution and oral administration over classical “orthosteric” drugs. This potential stems - may soon be viewed as the best life cycle management from their ability to offer greater selectivity and differ- strategy for protein therapeutics 2.
    [Show full text]
  • Biased Signaling of G Protein Coupled Receptors (Gpcrs): Molecular Determinants of GPCR/Transducer Selectivity and Therapeutic Potential
    Pharmacology & Therapeutics 200 (2019) 148–178 Contents lists available at ScienceDirect Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/pharmthera Biased signaling of G protein coupled receptors (GPCRs): Molecular determinants of GPCR/transducer selectivity and therapeutic potential Mohammad Seyedabadi a,b, Mohammad Hossein Ghahremani c, Paul R. Albert d,⁎ a Department of Pharmacology, School of Medicine, Bushehr University of Medical Sciences, Iran b Education Development Center, Bushehr University of Medical Sciences, Iran c Department of Toxicology–Pharmacology, School of Pharmacy, Tehran University of Medical Sciences, Iran d Ottawa Hospital Research Institute, Neuroscience, University of Ottawa, Canada article info abstract Available online 8 May 2019 G protein coupled receptors (GPCRs) convey signals across membranes via interaction with G proteins. Origi- nally, an individual GPCR was thought to signal through one G protein family, comprising cognate G proteins Keywords: that mediate canonical receptor signaling. However, several deviations from canonical signaling pathways for GPCR GPCRs have been described. It is now clear that GPCRs can engage with multiple G proteins and the line between Gprotein cognate and non-cognate signaling is increasingly blurred. Furthermore, GPCRs couple to non-G protein trans- β-arrestin ducers, including β-arrestins or other scaffold proteins, to initiate additional signaling cascades. Selectivity Biased Signaling Receptor/transducer selectivity is dictated by agonist-induced receptor conformations as well as by collateral fac- Therapeutic Potential tors. In particular, ligands stabilize distinct receptor conformations to preferentially activate certain pathways, designated ‘biased signaling’. In this regard, receptor sequence alignment and mutagenesis have helped to iden- tify key receptor domains for receptor/transducer specificity.
    [Show full text]
  • Cell Penetrating Peptides, Novel Vectors for Gene Therapy
    pharmaceutics Review Cell Penetrating Peptides, Novel Vectors for Gene Therapy Rebecca E. Taylor 1 and Maliha Zahid 2,* 1 Mechanical Engineering, Biomedical Engineering and Electrical and Computer Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, USA; [email protected] 2 Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15201, USA * Correspondence: [email protected]; Tel.: +1-412-692-8893; Fax: +1-412-692-6184 Received: 5 February 2020; Accepted: 1 March 2020; Published: 3 March 2020 Abstract: Cell penetrating peptides (CPPs), also known as protein transduction domains (PTDs), first identified ~25 years ago, are small, 6–30 amino acid long, synthetic, or naturally occurring peptides, able to carry variety of cargoes across the cellular membranes in an intact, functional form. Since their initial description and characterization, the field of cell penetrating peptides as vectors has exploded. The cargoes they can deliver range from other small peptides, full-length proteins, nucleic acids including RNA and DNA, liposomes, nanoparticles, and viral particles as well as radioisotopes and other fluorescent probes for imaging purposes. In this review, we will focus briefly on their history, classification system, and mechanism of transduction followed by a summary of the existing literature on use of CPPs as gene delivery vectors either in the form of modified viruses, plasmid DNA, small interfering RNA, oligonucleotides, full-length genes, DNA origami or peptide nucleic acids. Keywords: cell penetrating peptides; protein transduction domains; gene therapy; small interfering RNA 1. Introduction The plasma membrane of a cell is essential to its identity and survival, but at the same time presents a barrier to intracellular delivery of potentially diagnostic or therapeutic cargoes.
    [Show full text]
  • 1 Advances in Therapeutic Peptides Targeting G Protein-Coupled
    Advances in therapeutic peptides targeting G protein-coupled receptors Anthony P. Davenport1Ϯ Conor C.G. Scully2Ϯ, Chris de Graaf2, Alastair J. H. Brown2 and Janet J. Maguire1 1Experimental Medicine and Immunotherapeutics, Addenbrooke’s Hospital, University of Cambridge, CB2 0QQ, UK 2Sosei Heptares, Granta Park, Cambridge, CB21 6DG, UK. Ϯ Contributed equally Correspondence to Anthony P. Davenport email: [email protected] Abstract Dysregulation of peptide-activated pathways causes a range of diseases, fostering the discovery and clinical development of peptide drugs. Many endogenous peptides activate G protein-coupled receptors (GPCRs) — nearly fifty GPCR peptide drugs have been approved to date, most of them for metabolic disease or oncology, and more than 10 potentially first- in-class peptide therapeutics are in the pipeline. The majority of existing peptide therapeutics are agonists, which reflects the currently dominant strategy of modifying the endogenous peptide sequence of ligands for peptide-binding GPCRs. Increasingly, novel strategies are being employed to develop both agonists and antagonists, and both to introduce chemical novelty and improve drug-like properties. Pharmacodynamic improvements are evolving to bias ligands to activate specific downstream signalling pathways in order to optimise efficacy and reduce side effects. In pharmacokinetics, modifications that increase plasma-half life have been revolutionary. Here, we discuss the current status of peptide drugs targeting GPCRs, with a focus on evolving strategies to improve pharmacokinetic and pharmacodynamic properties. Introduction G protein-coupled receptors (GPCRs) mediate a wide range of signalling processes and are targeted by one third of drugs in clinical use1. Although most GPCR-targeting therapeutics are small molecules2, the endogenous ligands for many GPCRs are peptides (comprising 50 or fewer amino acids), which suggests that this class of molecule could be therapeutically useful.
    [Show full text]
  • Pepducins As a Potential Treatment Strategy for Asthma and COPD
    Thomas Jefferson University Jefferson Digital Commons Center for Translational Medicine Faculty Papers Center for Translational Medicine 6-1-2018 Pepducins as a potential treatment strategy for asthma and COPD. Reynold A. Panettieri Rutgers University - New Brunswick/Piscataway Tonio Pera Thomas Jefferson University Stephen B B. Liggett University of South Florida Jeffrey L. Benovic Thomas Jefferson University Raymond B. Penn Thomas Jefferson University Follow this and additional works at: https://jdc.jefferson.edu/transmedfp Part of the Translational Medical Research Commons Let us know how access to this document benefits ouy Recommended Citation Panettieri, Reynold A.; Pera, Tonio; Liggett, Stephen B B.; Benovic, Jeffrey L.; and Penn, Raymond B., "Pepducins as a potential treatment strategy for asthma and COPD." (2018). Center for Translational Medicine Faculty Papers. Paper 57. https://jdc.jefferson.edu/transmedfp/57 This Article is brought to you for free and open access by the Jefferson Digital Commons. The Jefferson Digital Commons is a service of Thomas Jefferson University's Center for Teaching and Learning (CTL). The Commons is a showcase for Jefferson books and journals, peer-reviewed scholarly publications, unique historical collections from the University archives, and teaching tools. The Jefferson Digital Commons allows researchers and interested readers anywhere in the world to learn about and keep up to date with Jefferson scholarship. This article has been accepted for inclusion in Center for Translational Medicine Faculty Papers by an authorized administrator of the Jefferson Digital Commons. For more information, please contact: [email protected]. HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Curr Opin Manuscript Author Pharmacol.
    [Show full text]
  • Chemotactic Ligands That Activate G-Protein-Coupled Formylpeptide Receptors
    International Journal of Molecular Sciences Review Chemotactic Ligands that Activate G-Protein-Coupled Formylpeptide Receptors Stacey A Krepel and Ji Ming Wang * Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA * Correspondence: [email protected]; Tel.: +1-301-846-6979 Received: 19 June 2019; Accepted: 5 July 2019; Published: 12 July 2019 Abstract: Leukocyte infiltration is a hallmark of inflammatory responses. This process depends on the bacterial and host tissue-derived chemotactic factors interacting with G-protein-coupled seven-transmembrane receptors (GPCRs) expressed on the cell surface. Formylpeptide receptors (FPRs in human and Fprs in mice) belong to the family of chemoattractant GPCRs that are critical mediators of myeloid cell trafficking in microbial infection, inflammation, immune responses and cancer progression. Both murine Fprs and human FPRs participate in many patho-physiological processes due to their expression on a variety of cell types in addition to myeloid cells. FPR contribution to numerous pathologies is in part due to its capacity to interact with a plethora of structurally diverse chemotactic ligands. One of the murine Fpr members, Fpr2, and its endogenous agonist peptide, Cathelicidin-related antimicrobial peptide (CRAMP), control normal mouse colon epithelial growth, repair and protection against inflammation-associated tumorigenesis. Recent developments in FPR (Fpr) and ligand studies have greatly expanded the scope of these receptors and ligands in host homeostasis and disease conditions, therefore helping to establish these molecules as potential targets for therapeutic intervention. Keywords: formyl peptide receptors; ligands; diseases 1. Properties of FPRs Formylpeptide receptors (FPR, Fpr for expression in mice) are G-protein-coupled receptors and were incidentally the first GPCRs to be identified in neutrophils [1].
    [Show full text]
  • Formyl Peptide Derived Lipopeptides Disclose Differences Between the Receptors in Mouse and Men and Call the Pepducin Concept in Question
    RESEARCH ARTICLE Formyl peptide derived lipopeptides disclose differences between the receptors in mouse and men and call the pepducin concept in question Malene Winther1, Andre Holdfeldt1, Martina Sundqvist1, Zahra Rajabkhani1, Michael Gabl1, Johan Bylund2, Claes Dahlgren1, Huamei Forsman1* a1111111111 1 Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, a1111111111 University of Gothenburg, Gothenburg, Sweden, 2 Department of Oral Microbiology and Immunology, a1111111111 Institute of Odontology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden a1111111111 a1111111111 * [email protected] Abstract OPEN ACCESS A pepducin is a lipopeptide containing a peptide sequence that is identical to one of the intra- Citation: Winther M, Holdfeldt A, Sundqvist M, cellular domains of the G-protein coupled receptor (GPCR) assumed to be the target. Neu- Rajabkhani Z, Gabl M, Bylund J, et al. (2017) trophils express two closely related formyl peptide receptors belonging to the family of Formyl peptide derived lipopeptides disclose GPCRs; FPR1 and FPR2 in human and their respective orthologue Fpr1 and Fpr2 in differences between the receptors in mouse and mouse. By applying the pepducin concept, we have earlier identified FPR2 activating pep- men and call the pepducin concept in question. PLoS ONE 12(9): e0185132. https://doi.org/ ducins generated from the third intracellular loop of FPR2. The third intracellular loop of 10.1371/journal.pone.0185132 FPR2 differs in two amino acids from that of FPR1, seven from Fpr2 and three from Fpr1. Editor: James Porter, University of North Dakota, Despite this, we found that pepducins generated from FPR1, FPR2, Fpr1 and Fpr2 all tar- UNITED STATES geted FPR2 in human neutrophils and Fpr2 in mouse, but with different modulating out- Received: May 25, 2017 comes.
    [Show full text]
  • For Peer Review Activation of the Wild-Type Receptor by Either Trypsin Or SLIGRL-NH 2 Is Accompanied by an Increase In
    British Journal of Pharmacology Page 2 of 49 BIASED SIGNALLING AND PROTEINASE-ACTIVATED RECEPTORS (PARS): TARGETING INFLAMMATORY DISEASE A,B Abbreviated title: Biased proteinase signalling and inflammation MD Hollenberg 1,2 , K Mihara 1 , D Polley 1 JY Suen 3, A Han 3, DP Fairlie 3 and R Ramachandran 1 1,2 Inflammation Research Network-Snyder Institute for Chronic Disease, 1Department of Physiology & Pharmacology and 2Department of Medicine, University of Calgary Faculty of Medicine, Calgary; AB Canada and 3Institute forFor Molecular Peer Bioscience, UniversityReview of Queensland, Brisbane, Queensland Australia A. Corresponding Author Morley D. Hollenberg Department of Physiology & Pharmacology University of Calgary Faculty of Medicine 3330 Hospital Drive NW Calgary AB Canada T2N 4N1 Phone: 403-220-6931 Fax: 403-270-0979 Email: [email protected] B. This article summarizes information presented at the Molecular Pharmacology of G Protein-Coupled Receptors 2012 meeting, Melbourne Australia 6-8 December, 2012 British Pharmacological Society Page 3 of 49 British Journal of Pharmacology 2 SUMMARY Although known since the 1960s that trypsin and chymotrypsin can mimic hormone action in tissues, it took until the 1990s to discover that serine proteinases can regulate cells by cleaving and activating a unique 4-member family of G-protein-coupled receptors termed ‘proteinase-activated-receptors’ or ‘PARs’. PAR activation involves the proteolytic exposure of an N-terminal receptor sequence, that folds back to function as a ‘tethered’ receptor-activating ligand (TL)’. A key N-terminal arginine in each of PARs 1 to 4 has been singled out as a target for cleavage by either thrombin (PARs 1, 3 and 4) or trypsin (PARs 2 and 4) to unmaskFor the TL that Peer activates sign allingReview via Gq, Gi or G12/13.
    [Show full text]
  • Physiology and Emerging Biochemistry of the Glucagon-Like Peptide-1 Receptor
    Hindawi Publishing Corporation Experimental Diabetes Research Volume 2012, Article ID 470851, 12 pages doi:10.1155/2012/470851 Review Article Physiology and Emerging Biochemistry of the Glucagon-Like Peptide-1 Receptor Francis S. Willard1 and Kyle W. Sloop2 1 Translational Science and Technologies, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA 2 Endocrine Discovery, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA Correspondence should be addressed to Kyle W. Sloop, sloop kyle [email protected] Received 31 December 2011; Accepted 25 January 2012 Academic Editor: Matteo Monami Copyright © 2012 F. S. Willard and K. W. Sloop. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The glucagon-like peptide-1 (GLP-1) receptor is one of the best validated therapeutic targets for the treatment of type 2 diabetes mellitus (T2DM). Over several years, the accumulation of basic, translational, and clinical research helped define the physiologic roles of GLP-1 and its receptor in regulating glucose homeostasis and energy metabolism. These efforts provided much of the foundation for pharmaceutical development of the GLP-1 receptor peptide agonists, exenatide and liraglutide, as novel medicines for patients suffering from T2DM. Now, much attention is focused on better understanding the molecular mechanisms involved in ligand induced signaling of the GLP-1 receptor. For example, advancements in biophysical and structural biology techniques are being applied in attempts to more precisely determine ligand binding and receptor occupancy characteristics at the atomic level.
    [Show full text]
  • Interdicting Gq Activation in Airway Disease by Receptor-Dependent and Receptor-Independent Mechanisms
    1521-0111/89/1/94–104$25.00 http://dx.doi.org/10.1124/mol.115.100339 MOLECULAR PHARMACOLOGY Mol Pharmacol 89:94–104, January 2016 Copyright ª 2015 by The American Society for Pharmacology and Experimental Therapeutics Interdicting Gq Activation in Airway Disease by Receptor-Dependent and Receptor-Independent Mechanisms Richard Carr III, Cynthia Koziol-White, Jie Zhang, Hong Lam, Steven S. An, Gregory G. Tall, Reynold A. Panettieri, Jr., and Jeffrey L. Benovic Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania (R.C., J.L.B.); Department of Medicine, Pulmonary, Allergy, and Critical Care Division, Airways Biology Initiative, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania (C.K.W., J.Z., R.A.P.); Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland (H.L., S.S.A.); and Department of Pharmacology and Downloaded from Physiology, University of Rochester Medical Center, Rochester, New York (G.G.T.) Received June 9, 2015; accepted October 9, 2015 ABSTRACT Ga bg heterotrimer (G ), an important mediator in the pathol- inhibits all G protein coupling to several G -coupled receptors, q q q molpharm.aspetjournals.org ogy of airway disease, plays a central role in bronchoconstric- including protease activated receptor 1, muscarinic acetylcho- tion and airway remodeling, including airway smooth muscle line M3, and histamine H1 receptors, while demonstrating no growth and inflammation. Current therapeutic strategies to direct effect on Gq. We also evaluated the ability of FR900359, treat airway disease include the use of muscarinic and leuko- also known as UBO-QIC, to directly inhibit Gq activation.
    [Show full text]
  • 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.
    [Show full text]
  • Concluding Remarks
    Concluding Remarks Volume 3 of the set of textbooks devoted to Circulatory and Ventilatory Sys- tems in the framework of Biomathematical and Biomechanical Modeling gives the basic knowledge on the first phases of signal transduction triggered by extracellular messengers. Signaling determines cell behavior. Numerous process can be modeled to quickly assess effects of parameters, all other agents remaining constant, once the mathematical model has been vali- dated. Advantage of mathematical models is to provide the complete quantity fields, whereas measurements are made in some points or corresponds to averages of ex- ploration windows of the field of the investigated variable. Mathematical description of large, complex biochemical reaction networks, in which molecules are nodes, and modeling of the dynamics of interactions (scaffold- ing, reaction, transcription, etc.) relies on computational simulations. A biochemical reaction network is defined by: (1) a set of variables — the state variables — that de- fine the state of the system and (2) rules of temporal changes and possible transport of involved variables. The network behavior can be analyzed in a single cells and extended to multicellular systems, especially in tumor models. Mathematical models of cascades of chemical reactions are aimed at describing evolution of molecular concentrations 1 using the mass action law or a reaction– diffusion equation set. A given reaction occurs with a certain probability. Stochastic models rely on a stochastic update of system variables. On the other hand, determin- istic models are carried out in systems with a large number of molecules, the time and variable states uniquely defining the state at the next time step.
    [Show full text]