Allosteric Modulator Leads Hiding in Plain Site: Developing Peptide and Peptidomimetics as GPCR Allosteric Modulators.
G-protein coupled receptor
allosteric modulators
biased signaling
drug discovery
nanobodies
pepducin
peptide
peptidomimetic
Journal
Frontiers in chemistry
ISSN: 2296-2646
Titre abrégé: Front Chem
Pays: Switzerland
ID NLM: 101627988
Informations de publication
Date de publication:
2021
2021
Historique:
received:
23
02
2021
accepted:
02
08
2021
entrez:
25
10
2021
pubmed:
26
10
2021
medline:
26
10
2021
Statut:
epublish
Résumé
Allosteric modulators (AMs) of G-protein coupled receptors (GPCRs) are desirable drug targets because they can produce fewer on-target side effects, improved selectivity, and better biological specificity (e.g., biased signaling or probe dependence) than orthosteric drugs. An underappreciated source for identifying AM leads are peptides and proteins-many of which were evolutionarily selected as AMs-derived from endogenous protein-protein interactions (e.g., transducer/accessory proteins), intramolecular receptor contacts (e.g., pepducins or extracellular domains), endogenous peptides, and exogenous libraries (e.g., nanobodies or conotoxins). Peptides offer distinct advantages over small molecules, including high affinity, good tolerability, and good bioactivity, and specific disadvantages, including relatively poor metabolic stability and bioavailability. Peptidomimetics are molecules that combine the advantages of both peptides and small molecules by mimicking the peptide's chemical features responsible for bioactivity while improving its druggability. This review 1) discusses sources and strategies to identify peptide/peptidomimetic AMs, 2) overviews strategies to convert a peptide lead into more drug-like "peptidomimetic," and 3) critically analyzes the advantages, disadvantages, and future directions of peptidomimetic AMs. While small molecules will and should play a vital role in AM drug discovery, peptidomimetics can complement and even exceed the advantages of small molecules, depending on the target, site, lead, and associated factors.
Identifiants
pubmed: 34692635
doi: 10.3389/fchem.2021.671483
pii: 671483
pmc: PMC8529114
doi:
Types de publication
Journal Article
Review
Langues
eng
Pagination
671483Subventions
Organisme : NIDA NIH HHS
ID : R37 DA039997
Pays : United States
Organisme : NIDA NIH HHS
ID : T32 DA007268
Pays : United States
Informations de copyright
Copyright © 2021 Olson, Traynor and Alt.
Déclaration de conflit d'intérêts
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Références
J Med Chem. 2011 Sep 8;54(17):6085-97
pubmed: 21774512
Org Biomol Chem. 2013 May 14;11(18):3030-7
pubmed: 23532512
Elife. 2018 Jun 22;7:
pubmed: 29932421
Int J Mol Sci. 2019 Dec 27;21(1):
pubmed: 31892275
Arterioscler Thromb Vasc Biol. 2016 Jan;36(1):189-97
pubmed: 26681756
J Med Chem. 1993 Jan 22;36(2):256-63
pubmed: 8093736
BMC Genomics. 2017 Oct 17;18(1):797
pubmed: 29041922
J Med Chem. 2004 Dec 16;47(26):6595-602
pubmed: 15588094
Mol Pharmacol. 2018 Aug;94(2):850-861
pubmed: 29769246
Nat Med. 2002 Oct;8(10):1161-5
pubmed: 12357249
Mol Pharmacol. 2019 Dec;96(6):737-752
pubmed: 31548340
Proc Natl Acad Sci U S A. 2013 Sep 3;110(36):E3445-54
pubmed: 23946421
Pain. 2021 Jul 09;:
pubmed: 34252907
Trends Pharmacol Sci. 2021 Mar;42(3):135-150
pubmed: 33358695
Biochem Biophys Res Commun. 2020 Mar 26;524(1):156-162
pubmed: 31982133
Proc Natl Acad Sci U S A. 2015 Feb 10;112(6):1761-6
pubmed: 25624485
Curr Pharm Des. 2010;16(28):3071-88
pubmed: 20687879
Trends Pharmacol Sci. 2021 Apr;42(4):283-299
pubmed: 33581873
Drug Discov Today Technol. 2012 Spring;9(1):e1-e70
pubmed: 24064242
Life Sci. 2003 Dec 5;74(2-3):255-62
pubmed: 14607253
Cell. 2009 Apr 17;137(2):332-43
pubmed: 19379698
Cell Discov. 2016 May 17;2:16012
pubmed: 27462459
Mol Pharmacol. 2009 Jan;75(1):44-59
pubmed: 18923064
Sci Rep. 2015 Aug 20;5:13264
pubmed: 26290113
Front Pharmacol. 2019 Oct 25;10:1258
pubmed: 31708782
Nat Rev Drug Discov. 2013 Mar;12(3):205-16
pubmed: 23411724
Front Mol Biosci. 2018 Nov 16;5:100
pubmed: 30505835
Drug Discov Today. 2021 Apr;26(4):1097-1105
pubmed: 33497830
J Med Chem. 2015 Jun 11;58(11):4624-37
pubmed: 25984647
Drug Discov Today. 2017 Feb;22(2):454-462
pubmed: 27856346
Physiol Res. 2004;53(6):603-7
pubmed: 15588127
Mol Psychiatry. 2014 Sep;19(9):986-94
pubmed: 24061495
Br J Pharmacol. 2013 Feb;168(4):807-21
pubmed: 22994258
Chem Rev. 2004 Dec;104(12):6085-117
pubmed: 15584696
Chem Rev. 2019 Sep 11;119(17):9836-9860
pubmed: 30990310
Toxins (Basel). 2017 Nov 16;9(11):
pubmed: 29144441
J Med Chem. 2009 Apr 9;52(7):2043-51
pubmed: 19271750
Curr Opin Chem Biol. 2008 Jun;12(3):292-6
pubmed: 18423417
Handb Exp Pharmacol. 2017;244:163-175
pubmed: 28667477
Mol Pharmacol. 2018 Apr;93(4):251-258
pubmed: 29298813
Pharmacology. 1993 Dec;47(6):351-9
pubmed: 7506424
Expert Opin Drug Discov. 2017 Jun;12(6):611-623
pubmed: 28398099
J Biol Chem. 2015 Jun 19;290(25):15785-15798
pubmed: 25934391
Biochem Biophys Res Commun. 1994 Jul 15;202(1):410-5
pubmed: 8037741
Angew Chem Int Ed Engl. 2010 Sep 3;49(37):6545-8
pubmed: 20533477
J Med Chem. 2017 Dec 14;60(23):9838-9859
pubmed: 29131958
J Am Chem Soc. 2011 Oct 12;133(40):15878-81
pubmed: 21905700
Cell. 2019 Aug 8;178(4):1030
pubmed: 31398329
Peptides. 2013 Feb;40:72-6
pubmed: 23270674
Chem Biol Drug Des. 2010 Sep 1;76(3):201-17
pubmed: 20626410
Methods Enzymol. 2018;610:117-134
pubmed: 30390796
Annu Rev Pharmacol Toxicol. 2017 Jan 6;57:19-37
pubmed: 27959623
PLoS One. 2019 Jun 6;14(6):e0217371
pubmed: 31170174
Cell Mol Life Sci. 2005 Mar;62(5):551-77
pubmed: 15747061
Pharmaceuticals (Basel). 2012 Feb 16;5(2):209-35
pubmed: 24288089
Nat Chem Biol. 2007 Feb;3(2):108-12
pubmed: 17220901
Mol Cell Endocrinol. 2019 Apr 15;486:89-95
pubmed: 30849406
J Neurochem. 1999 Dec;73(6):2617-20
pubmed: 10582626
J Biol Chem. 2013 Jan 18;288(3):1814-27
pubmed: 23184947
Nature. 2011 Jul 19;477(7366):549-55
pubmed: 21772288
J Med Chem. 2018 Jul 26;61(14):6075-6086
pubmed: 29939746
Nature. 2015 Aug 20;524(7565):315-21
pubmed: 26245379
Bioorg Med Chem. 2018 Jun 1;26(10):2700-2707
pubmed: 28720325
J Med Chem. 1993 Aug 6;36(16):2356-61
pubmed: 8103113
J Med Chem. 2018 Feb 22;61(4):1382-1414
pubmed: 28737935
Structure. 2019 Dec 3;27(12):1862-1874.e7
pubmed: 31669042
Evid Based Complement Alternat Med. 2013;2013:563716
pubmed: 23956775
Nat Commun. 2018 Sep 13;9(1):3712
pubmed: 30213947
Mol Pharmacol. 2003 Jan;63(1):26-35
pubmed: 12488533
Nature. 2015 Aug 13;524(7564):173-179
pubmed: 26147082
J Neurosci. 2008 Oct 22;28(43):10943-51
pubmed: 18945902
Nat Commun. 2020 Feb 5;11(1):711
pubmed: 32024829
Nat Neurosci. 2001 Sep;4(9):902-7
pubmed: 11528421
Mol Pharmacol. 1996 Oct;50(4):752-62
pubmed: 8863819
Nature. 2013 May 2;497(7447):137-41
pubmed: 23604254
Science. 2020 Jul 10;369(6500):161-167
pubmed: 32646996
Yale J Biol Med. 2017 Mar 29;90(1):97-110
pubmed: 28356897
Toxins (Basel). 2020 Aug 06;12(8):
pubmed: 32781580
Nature. 2016 Jul 21;535(7612):448-52
pubmed: 27409812
J Biol Chem. 2014 Dec 26;289(52):35668-84
pubmed: 25395624
Nat Commun. 2020 Jun 23;11(1):3183
pubmed: 32576815
Pharmacol Rev. 2013 Feb 13;65(2):545-77
pubmed: 23406670
Eur Neuropsychopharmacol. 2013 Mar;23(3):253-62
pubmed: 22658400
J Biol Chem. 2011 Sep 9;286(36):31661-75
pubmed: 21685390
Am J Physiol Regul Integr Comp Physiol. 2013 Jan 1;304(1):R10-22
pubmed: 23152113
Mol Pharmacol. 2016 Jan;89(1):94-104
pubmed: 26464325
Angew Chem Int Ed Engl. 2016 Apr 4;55(15):4692-6
pubmed: 26948522
J Med Chem. 2018 Nov 21;61(22):10198-10205
pubmed: 30358401
Proc Natl Acad Sci U S A. 2010 Dec 21;107(51):22255-9
pubmed: 21139054
Science. 2019 Jun 28;364(6447):1283-1287
pubmed: 31249059
Nature. 1991 Nov 7;354(6348):82-4
pubmed: 1944576
Biochim Biophys Acta. 2013 Jul;1828(7):1619-28
pubmed: 23380425
Nucleic Acids Res. 2020 Jan 8;48(D1):D394-D401
pubmed: 31665428
Front Behav Neurosci. 2018 Dec 12;12:302
pubmed: 30618660
Behav Brain Res. 1996;73(1-2):313-17
pubmed: 8788526
Am J Physiol Regul Integr Comp Physiol. 2009 Oct;297(4):R1009-18
pubmed: 19641130
J Am Chem Soc. 1973 Oct 31;95(22):7523-4
pubmed: 4747887
Beilstein J Org Chem. 2013;9:204-14
pubmed: 23400263
J Med Chem. 2019 Jan 10;62(1):88-127
pubmed: 30106578
Am J Pathol. 2011 Jul;179(1):513-23
pubmed: 21703428
Eur J Pharmacol. 2004 Mar 8;487(1-3):65-72
pubmed: 15033377
Org Biomol Chem. 2008 May 7;6(9):1647-54
pubmed: 18421399
Biochem Pharmacol. 2020 Oct;180:114143
pubmed: 32653592
Semin Perinatol. 2002 Dec;26(6):389-97
pubmed: 12537309
Curr Opin Cell Biol. 2019 Apr;57:115-122
pubmed: 30849632
PLoS One. 2012;7(6):e39166
pubmed: 22720062
Trends Pharmacol Sci. 2019 May;40(5):309-326
pubmed: 30955896
Circulation. 2006 Mar 7;113(9):1244-54
pubmed: 16505172
Nat Chem. 2011 Jun 23;3(7):509-24
pubmed: 21697871
Arterioscler Thromb Vasc Biol. 2020 Dec;40(12):2990-3003
pubmed: 33028101
Mol Pharmacol. 2015 Feb;87(2):240-50
pubmed: 25425625
J Med Chem. 2019 Jan 10;62(1):24-45
pubmed: 29457894
J Med Chem. 1988 Jul;31(7):1430-6
pubmed: 3385734
J Biol Chem. 2010 Aug 13;285(33):25624-36
pubmed: 20551320
Proc Natl Acad Sci U S A. 2013 Dec 24;110(52):E5088-97
pubmed: 24309376
Pharmacol Res. 2015 Sep;99:370-6
pubmed: 26211948
Peptides. 1997;18(8):1209-15
pubmed: 9396063
Bioorg Med Chem. 2020 Sep 15;28(18):115676
pubmed: 32828432
Adv Exp Med Biol. 2009;611:271-3
pubmed: 19400189
Chem Rev. 2016 Jun 8;116(11):6707-41
pubmed: 26882314
Acc Chem Res. 2008 Oct;41(10):1278-88
pubmed: 18412373
Schizophr Res. 2011 Jan;125(1):88-92
pubmed: 21036015
J Am Chem Soc. 2011 Jul 6;133(26):10184-94
pubmed: 21609016
Nature. 2017 Aug 24;548(7668):480-484
pubmed: 28813418
J Biol Chem. 2006 Aug 11;281(32):23254-63
pubmed: 16754662
Nat Med. 2005 Jun;11(6):661-5
pubmed: 15880119
Chem Sci. 2016 Apr 21;7(4):2492-2500
pubmed: 28660018
J Neurosci. 2013 Jan 23;33(4):1615-30
pubmed: 23345234
J Biol Chem. 2003 Mar 7;278(10):8547-55
pubmed: 12500972
Theranostics. 2018 Sep 09;8(17):4664-4678
pubmed: 30279730
Chem Rev. 2019 Nov 13;119(21):11510-11549
pubmed: 31633928
Biochem Pharmacol. 2012 Mar 1;83(5):608-15
pubmed: 22197588
Beilstein J Org Chem. 2014 May 22;10:1197-212
pubmed: 24991269
J Biol Chem. 2003 Jan 10;278(2):896-907
pubmed: 12417595
Mol Endocrinol. 2005 Sep;19(9):2400-11
pubmed: 15905359
Proc Natl Acad Sci U S A. 2002 Jan 22;99(2):643-8
pubmed: 11805322
Bioorg Med Chem Lett. 2014 Oct 15;24(20):4871-5
pubmed: 25241924
J Biol Chem. 1999 Dec 3;274(49):34911-5
pubmed: 10574965
Mol Pharmacol. 2001 Oct;60(4):725-31
pubmed: 11562434
Adv Drug Deliv Rev. 2005 Feb 28;57(4):559-77
pubmed: 15722164
J Neurochem. 1988 Mar;50(3):960-8
pubmed: 2892892
Br J Pharmacol. 2015 Jan;172(2):277-86
pubmed: 24460691
Protein Sci. 2019 Feb;28(2):305-312
pubmed: 30345641
J Med Chem. 2015 Nov 12;58(21):8573-83
pubmed: 26465170
Biochim Biophys Acta Biomembr. 2020 Mar 1;1862(3):183174
pubmed: 31887275
ACS Chem Biol. 2018 Jun 15;13(6):1577-1587
pubmed: 29746088
Chem Soc Rev. 2020 Jun 7;49(11):3262-3277
pubmed: 32255135
Nat Med. 2006 Mar;12(3):324-9
pubmed: 16474401
Neuropharmacology. 2019 Jul 1;152:67-77
pubmed: 30445101
Biochem Biophys Res Commun. 1971 Jun 18;43(6):1376-81
pubmed: 4398196
Toxicon. 2011 Nov;58(6-7):455-63
pubmed: 21906611
Curr Med Chem. 2004 Nov;11(21):2799-822
pubmed: 15544477
Circulation. 2012 Jul 3;126(1):83-91
pubmed: 22705889
J Med Chem. 2019 May 9;62(9):4500-4525
pubmed: 30932486
Neuron. 2011 Jan 13;69(1):120-31
pubmed: 21220103
Expert Opin Biol Ther. 2020 Aug;20(8):925-935
pubmed: 32264722
Neuropharmacology. 2017 Dec;127:116-123
pubmed: 28533165
J Pharmacol Exp Ther. 2021 Sep;378(3):287-299
pubmed: 34183434
Chem Biol Drug Des. 2013 Jan;81(1):148-65
pubmed: 23253136
Proc Natl Acad Sci U S A. 2017 Feb 14;114(7):1708-1713
pubmed: 28130548
J Biol Chem. 2003 Sep 5;278(36):34451-7
pubmed: 12824165
Sci Rep. 2017 Aug 25;7(1):9560
pubmed: 28842619
Neuropharmacology. 2021 Feb 1;183:108406
pubmed: 33212113
Nat Rev Drug Discov. 2013 Aug;12(8):630-44
pubmed: 23903222
Biochem Pharmacol. 2011 Mar 15;81(6):691-702
pubmed: 21184747
Biochim Biophys Acta Biomembr. 2021 Jan 1;1863(1):183492
pubmed: 33065137
Biopolymers. 1997;43(3):219-66
pubmed: 9277134
Blood. 2012 Feb 16;119(7):1717-25
pubmed: 22186993
Org Biomol Chem. 2007 Nov 21;5(22):3577-85
pubmed: 17971985
J Pharmacol Sci. 2018 May;137(1):67-75
pubmed: 29716811