Generic placeholder image

Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Review Article

γ-AApeptides as a New Strategy for Therapeutic Development

Author(s): Alekhya Nimmagadda, Yan Shi and Jianfeng Cai*

Volume 26, Issue 13, 2019

Page: [2313 - 2329] Pages: 17

DOI: 10.2174/0929867324666171107095913

Price: $65

Abstract

A new class of peptidomimetics termed as "γ-AApeptides" was recently developed by our group. Similar to other peptidomimetics, γ-AApeptides are resistant to proteolytic degradation, and possess limitless potential to introduce chemically diverse functional groups. γ-AApeptides have shown great promise in biomedical applications. In this article, we will review a few examples of γ-AApeptides with biological potential. Certain γ-AApeptides can permeate cell membranes and therefore they can be used as potential drug carrier. γ-AApeptides can also bind to HIV RNA with high specificity and affinity, suggesting their potential application as anti-HIV agents. Moreover, they can mimic host-defense peptides and display potent and broad-spectrum activity towards a range of drug-resistant bacterial pathogens. They are also potential anti-cancer agents. For instance, they have shown great promise in targeted imaging of tumor in mouse model, and they are also capable of disrupting p53/DNA interactions, and thus antagonize STAT3 signaling pathway. Recently, from combinatorial screening, γ-AApeptides are identified to inhibit Aβ peptide aggregation, and thus they can be developed into potential anti- Alzheimer’s disease agent.

Keywords: γ-AApeptides, peptidomimetics, structures, anticancer activity, antimicrobial activity, anti-HIV activity, anti-Aβ aggregation.

[1]
Wu, Y-D.; Gellman, S. Peptidomimetics. Acc. Chem. Res., 2008, 41(10), 1231-1232. [http://dx.doi.org/10.1021/ar800216e]. [PMID: 18937394].
[2]
Goodman, C.M.; Choi, S.; Shandler, S.; DeGrado, W.F. Foldamers as versatile frameworks for the design and evolution of function. Nat. Chem. Biol., 2007, 3(5), 252-262. [http://dx.doi.org/10.1038/nchembio876]. [PMID: 17438550].
[3]
Patch, J.A.; Barron, A.E. Mimicry of bioactive peptides via non-natural, sequence-specific peptidomimetic oligomers. Curr. Opin. Chem. Biol., 2002, 6(6), 872-877. [http://dx.doi.org/10.1016/S1367-5931(02)00385-X]. [PMID: 12470744].
[4]
Cheng, R.P.; Gellman, S.H.; DeGrado, W.F. β-Peptides: From structure to function. Chem. Rev., 2001, 101(10), 3219-3232. [http://dx.doi.org/10.1021/cr000045i]. [PMID: 11710070].
[5]
Horne, W.S.; Johnson, L.M.; Ketas, T.J.; Klasse, P.J.; Lu, M.; Moore, J.P.; Gellman, S.H. Structural and biological mimicry of protein surface recognition by α/β-peptide foldamers. Proc. Natl. Acad. Sci. USA, 2009, 106(35), 14751-14756. [http://dx.doi.org/10.1073/pnas.0902663106]. [PMID: 19706443].
[6]
Laursen, J.S.; Engel-Andreasen, J.; Olsen, C.A. β-peptoid foldamers at Last. Acc. Chem. Res., 2015, 48(10), 2696-2704. [http://dx.doi.org/10.1021/acs.accounts.5b00257]. [PMID: 26176689].
[7]
Simon, R.J.; Kania, R.S.; Zuckermann, R.N.; Huebner, V.D.; Jewell, D.A.; Banville, S.; Ng, S.; Wang, L.; Rosenberg, S.; Marlowe, C.K. Peptoids: a modular approach to drug discovery. Proc. Natl. Acad. Sci. USA, 1992, 89(20), 9367-9371. [http://dx.doi.org/10.1073/pnas.89.20.9367]. [PMID: 1409642].
[8]
Fremaux, J.; Kauffmann, B.; Guichard, G. Synthesis and folding propensity of aliphatic oligoureas containing repeats of proline-type units. J. Org. Chem., 2014, 79(12), 5494-5502. [http://dx.doi.org/10.1021/jo5006075]. [PMID: 24810879].
[9]
Teng, P.; Shi, Y.; Sang, P.; Cai, J. γ-AApeptides as a New Class of Peptidomimetics. Chemistry, 2016, 22(16), 5458-5466. [http://dx.doi.org/10.1002/chem.201504936]. [PMID: 26945679].
[10]
Shi, Y.; Teng, P.; Sang, P.; She, F.; Wei, L.; Cai, J. γ-AApeptides: Design, structure, and applications. Acc. Chem. Res., 2016, 49(3), 428-441. [http://dx.doi.org/10.1021/acs.accounts.5b00492]. [PMID: 26900964].
[11]
Dragulescu-Andrasi, A.; Rapireddy, S.; Frezza, B.M.; Gayathri, C.; Gil, R.R.; Ly, D.H. A simple γ-backbone modification preorganizes peptide nucleic acid into a helical structure. J. Am. Chem. Soc., 2006, 128(31), 10258-10267. [http://dx.doi.org/10.1021/ja0625576]. [PMID: 16881656].
[12]
Winssinger, N.; Damoiseaux, R.; Tully, D.C.; Geierstanger, B.H.; Burdick, K.; Harris, J.L. PNA-encoded protease substrate microarrays. Chem. Biol., 2004, 11(10), 1351-1360. [http://dx.doi.org/10.1016/j.chembiol.2004.07.015]. [PMID: 15489162].
[13]
Debaene, F.; Da Silva, J.A.; Pianowski, Z.; Duran, F.J.; Winssinger, N. Expanding the scope of PNA-encoded libraries: divergent synthesis of libraries targeting cysteine, serine and metallo-proteases as well as tyrosine phosphatases. Tetrahedron, 2007, 63(28), 6577-6586. [http://dx.doi.org/10.1016/j.tet.2007.03.033].
[14]
Niu, Y.; Hu, Y.; Li, X.; Chen, J.; Cai, J. [gamma]-AApeptides: Design, synthesis and evaluation. New J. Chem., 2011, 35(3), 542-545. [http://dx.doi.org/10.1039/c0nj00943a].
[15]
Wu, H.; Amin, M.N.; Niu, Y.; Qiao, Q.; Harfouch, N.; Nimer, A.; Cai, J. Solid-phase synthesis of γ-AApeptides using a submonomeric approach. Org. Lett., 2012, 14(13), 3446-3449. [http://dx.doi.org/10.1021/ol301406a]. [PMID: 22731678].
[16]
Wu, H.; Teng, P.; Cai, J. Rapid access to multiple classes of peptidomimetics from common γ-aapeptide building blocks. Eur. J. Org. Chem., 2014, 2014(8), 1760-1765. [http://dx.doi.org/10.1002/ejoc.201301841].
[17]
Wu, H.; She, F.; Gao, W.; Prince, A.; Li, Y.; Wei, L.; Mercer, A.; Wojtas, L.; Ma, S.; Cai, J. The synthesis of head-to-tail cyclic sulfono-γ-AApeptides. Org. Biomol. Chem., 2015, 13(3), 672-676. [http://dx.doi.org/10.1039/C4OB02232G]. [PMID: 25420701].
[18]
Schwergold, C.; Depecker, G.; Giorgio, C.D.; Patino, N.; Jossinet, F.; Ehresmann, B.; Terreux, R.; Cabrol-Bass, D.; Condom, R. Cyclic PNA hexamer-based compound: Modelling, synthesis and inhibition of the HIV-1 RNA dimerization process. Tetrahedron, 2002, 58(28), 5675-5687. [http://dx.doi.org/10.1016/S0040-4020(02)00527-6].
[19]
Wu, H.; Niu, Y.; Padhee, S.; Wang, R.E.; Li, Y.; Qiao, Q.; Bai, G.; Cao, C.; Cai, J. Design and synthesis of unprecedented cyclic[gamma]-AApeptides for antimicrobial development. Chem. Sci. (Camb.), 2012, 3(8), 2570-2575. [http://dx.doi.org/10.1039/c2sc20428b].
[20]
Gellman, S.H. Foldamers: A Manifesto. Acc. Chem. Res., 1998, 31, 173-180. [http://dx.doi.org/10.1021/ar960298r].
[21]
Gennari, C.; Gude, M.; Potenza, D.; Piarulli, U. Hydrogen-bonding donor/acceptor scales in β-sulfonamidopeptides. Chemistry, 1998, 4, 1924-1931. [http://dx.doi.org/10.1002/(SICI)1521-3765(19981002)4:10<1924:AID-CHEM1924>3.0.CO;2-P].
[22]
Karlsson, A.J.; Pomerantz, W.C.; Weisblum, B.; Gellman, S.H.; Palecek, S.P. Antifungal activity from 14-helical β-peptides. J. Am. Chem. Soc., 2006, 128(39), 12630-12631. [http://dx.doi.org/10.1021/ja064630y]. [PMID: 17002340].
[23]
Wu, H.; Qiao, Q.; Hu, Y.; Teng, P.; Gao, W.; Zuo, X.; Wojtas, L.; Larsen, R.W.; Ma, S.; Cai, J. Sulfono-γ-AApeptides as a new class of nonnatural helical foldamer. Chemistry, 2015, 21(6), 2501-2507. [http://dx.doi.org/10.1002/chem.201406112]. [PMID: 25504756].
[24]
Wu, H.; Qiao, Q.; Teng, P.; Hu, Y.; Antoniadis, D.; Zuo, X.; Cai, J. New class of heterogeneous helical peptidomimetics. Org. Lett., 2015, 17(14), 3524-3527. [http://dx.doi.org/10.1021/acs.orglett.5b01608]. [PMID: 26153619].
[25]
Cai, W.; Chen, X. Anti-angiogenic cancer therapy based on integrin alphavbeta3 antagonism. Anticancer. Agents Med. Chem., 2006, 6(5), 407-428. [http://dx.doi.org/10.2174/187152006778226530]. [PMID: 17017851].
[26]
Yang, Y.; Niu, Y.; Hong, H.; Wu, H.; Zhang, Y.; Engle, J.W.; Barnhart, T.E.; Cai, J.; Cai, W. Radiolabeled γ-AApeptides: A new class of tracers for positron emission tomography. Chem. Commun. (Camb.), 2012, 48(63), 7850-7852. [http://dx.doi.org/10.1039/c2cc33620k]. [PMID: 22785080].
[27]
He, R.; Tan, L.; Browning, D.D.; Wang, J.M.; Ye, R.D. The synthetic peptide Trp-Lys-Tyr-Met-Val-D-Met is a potent chemotactic agonist for mouse formyl peptide receptor. J. Immunol., 2000, 165(8), 4598-4605. [http://dx.doi.org/10.4049/jimmunol.165.8.4598]. [PMID: 11035102].
[28]
Giordano, C.; Lucente, G.; Masi, A.; Paradisi, M.P.; Sansone, A.; Spisani, S. α-peptide/β-sulfonamidopeptide hybrids: Analogs of the chemotactic agent for-Met-Leu-Phe-OMe. Bioorg. Med. Chem., 2006, 14(8), 2642-2652. [http://dx.doi.org/10.1016/j.bmc.2005.11.043]. [PMID: 16356729].
[29]
Torino, D.; Mollica, A.; Pinnen, F.; Feliciani, F.; Spisani, S.; Lucente, G. Novel chemotactic For-Met-Leu-Phe-OMe (fMLF-OMe) analogues based on met residue replacement by 4-amino-proline scaffold: Synthesis and bioactivity. Bioorg. Med. Chem., 2009, 17(1), 251-259. [http://dx.doi.org/10.1016/j.bmc.2008.11.010]. [PMID: 19081258].
[30]
Hu, Y.; Cheng, N.; Wu, H.; Kang, S.; Ye, R.D.; Cai, J. Design, synthesis and characterization of fMLF-mimicking AApeptides. ChemBioChem, 2014, 15(16), 2420-2426. [http://dx.doi.org/10.1002/cbic.201402396]. [PMID: 25224835].
[31]
Murray, J.K.; Gellman, S.H. Targeting protein-protein interactions: Lessons from p53/MDM2. Biopolymers, 2007, 88(5), 657-686. [http://dx.doi.org/10.1002/bip.20741]. [PMID: 17427181].
[32]
Debnath, B.; Xu, S.; Neamati, N. Small molecule inhibitors of signal transducer and activator of transcription 3 (Stat3) protein. J. Med. Chem., 2012, 55(15), 6645-6668. [http://dx.doi.org/10.1021/jm300207s]. [PMID: 22650325].
[33]
Siddiquee, K.A.; Gunning, P.T.; Glenn, M.; Katt, W.P.; Zhang, S.; Schrock, C.; Sebti, S.M.; Jove, R.; Hamilton, A.D.; Turkson, J. An oxazole-based small-molecule stat3 inhibitor modulates stat3 stability and processing and induces antitumor cell effects. ACS Chem. Biol., 2009, 4, 309-309. [http://dx.doi.org/10.1021/cb9000684]. [PMID: 18154266].
[34]
Fletcher, S.; Page, B.D.; Zhang, X.; Yue, P.; Li, Z.H.; Sharmeen, S.; Singh, J.; Zhao, W.; Schimmer, A.D.; Trudel, S.; Turkson, J.; Gunning, P.T. Antagonism of the Stat3-Stat3 protein dimer with salicylic acid based small molecules. ChemMedChem, 2011, 6(8), 1459-1470. [http://dx.doi.org/10.1002/cmdc.201100194]. [PMID: 21618433].
[35]
Teng, P.; Zhang, X.; Wu, H.; Qiao, Q.; Sebti, S.M.; Cai, J. Identification of novel inhibitors that disrupt STAT3-DNA interaction from a γ-AApeptide OBOC combinatorial library. Chem. Commun. (Camb.), 2014, 50(63), 8739-8742. [http://dx.doi.org/10.1039/C4CC03909B]. [PMID: 24964402].
[36]
Niu, Y.; Wang, R.E.; Wu, H.; Cai, J. Recent development of small antimicrobial peptidomimetics. Future Med. Chem., 2012, 4(14), 1853-1862. [http://dx.doi.org/10.4155/fmc.12.111]. [PMID: 23043481].
[37]
Marr, A.K.; Gooderham, W.J.; Hancock, R.E. Antibacterial peptides for therapeutic use: Obstacles and realistic outlook. Curr. Opin. Pharmacol., 2006, 6(5), 468-472. [http://dx.doi.org/10.1016/j.coph.2006.04.006]. [PMID: 16890021].
[38]
Karlsson, A.J.; Pomerantz, W.C.; Weisblum, B.; Gellman, S.H.; Palecek, S.P. Antifungal activity from 14-helical beta-peptides. J. Am. Chem. Soc., 2006, 128(39), 12630-12631. [http://dx.doi.org/10.1021/ja064630y]. [PMID: 17002340].
[39]
Patch, J.A.; Barron, A.E. Helical peptoid mimics of magainin-2 amide. J. Am. Chem. Soc., 2003, 125(40), 12092-12093. [http://dx.doi.org/10.1021/ja037320d]. [PMID: 14518985].
[40]
Niu, Y.; Padhee, S.; Wu, H.; Bai, G.; Harrington, L.; Burda, W.N.; Shaw, L.N.; Cao, C.; Cai, J. Identification of γ-AApeptides with potent and broad-spectrum antimicrobial activity. Chem. Commun. (Camb.), 2011, 47(44), 12197-12199. [http://dx.doi.org/10.1039/c1cc14476f]. [PMID: 21963627].
[41]
Chen, C.; Pan, F.; Zhang, S.; Hu, J.; Cao, M.; Wang, J.; Xu, H.; Zhao, X.; Lu, J.R. Antibacterial activities of short designer peptides: a link between propensity for nanostructuring and capacity for membrane destabilization. Biomacromolecules, 2010, 11(2), 402-411. [http://dx.doi.org/10.1021/bm901130u]. [PMID: 20078032].
[42]
Matsuzaki, K. Magainins as paradigm for the mode of action of pore forming polypeptides. Biochim. Biophys. Acta, 1998, 1376(3), 391-400. [http://dx.doi.org/10.1016/S0304-4157(98)00014-8]. [PMID: 9804997].
[43]
Li, Y.; Wu, H.; Teng, P.; Bai, G.; Lin, X.; Zuo, X.; Cao, C.; Cai, J. Helical antimicrobial sulfono-γ-aapeptides. J. Med. Chem., 2015, 58(11), 4802-4811. [http://dx.doi.org/10.1021/acs.jmedchem.5b00537]. [PMID: 26020456].
[44]
Li, Y.; Smith, C.; Wu, H.; Teng, P.; Shi, Y.; Padhee, S.; Jones, T.; Nguyen, A-M.; Cao, C.; Yin, H.; Cai, J. Short antimicrobial lipo-α/γ-AA hybrid peptides. ChemBioChem, 2014, 15(15), 2275-2280. [http://dx.doi.org/10.1002/cbic.201402264]. [PMID: 25169879].
[45]
Obrecht, D.; Robinson, J.A.; Bernardini, F.; Bisang, C.; DeMarco, S.J.; Moehle, K.; Gombert, F.O. Recent progress in the discovery of macrocyclic compounds as potential anti-infective therapeutics. Curr. Med. Chem., 2009, 16(1), 42-65. [http://dx.doi.org/10.2174/092986709787002844]. [PMID: 19149562].
[46]
Makovitzki, A.; Avrahami, D.; Shai, Y. Ultrashort antibacterial and antifungal lipopeptides. Proc. Natl. Acad. Sci. USA, 2006, 103(43), 15997-16002. [http://dx.doi.org/10.1073/pnas.0606129103]. [PMID: 17038500].
[47]
Makovitzki, A.; Baram, J.; Shai, Y. Antimicrobial lipopolypeptides composed of palmitoyl Di- and tricationic peptides: In vitro and in vivo activities, self-assembly to nanostructures, and a plausible mode of action. Biochemistry, 2008, 47(40), 10630-10636. [http://dx.doi.org/10.1021/bi8011675]. [PMID: 18783248].
[48]
Niu, Y.; Padhee, S.; Wu, H.; Bai, G.; Qiao, Q.; Hu, Y.; Harrington, L.; Burda, W.N.; Shaw, L.N.; Cao, C.; Cai, J. Lipo-γ-AApeptides as a new class of potent and broad-spectrum antimicrobial agents. J. Med. Chem., 2012, 55(8), 4003-4009. [http://dx.doi.org/10.1021/jm300274p]. [PMID: 22475244].
[49]
Li, Y.; Smith, C.; Wu, H.; Teng, P.; Shi, Y.; Padhee, S.; Jones, T.; Nguyen, A-M.; Cao, C.; Yin, H.; Cai, J. Short antimicrobial lipo-α/γ-AA hybrid peptides. ChemBioChem, 2014, 15(15), 2275-2280. [http://dx.doi.org/10.1002/cbic.201402264]. [PMID: 25169879].
[50]
Li, Y.; Smith, C.; Wu, H.; Padhee, S.; Manoj, N.; Cardiello, J.; Qiao, Q.; Cao, C.; Yin, H.; Cai, J. Lipidated cyclic γ-AApeptides display both antimicrobial and anti-inflammatory activity. ACS Chem. Biol., 2014, 9(1), 211-217. [http://dx.doi.org/10.1021/cb4006613]. [PMID: 24144063].
[51]
Padhee, S.; Li, Y.; Cai, J. Activity of lipo-cyclic γ-AApeptides against biofilms of Staphylococcus epidermidis and Pseudomonas aeruginosa. Bioorg. Med. Chem. Lett., 2015, 25(12), 2565-2569. [http://dx.doi.org/10.1016/j.bmcl.2015.04.039]. [PMID: 25977094].
[52]
Wu, H.; Li, Y.; Bai, G.; Niu, Y.; Qiao, Q.; Tipton, J.D.; Cao, C.; Cai, J. γ-AApeptide-based small-molecule ligands that inhibit Aβ aggregation. Chem. Commun. (Camb.), 2014, 50(40), 5206-5208. [http://dx.doi.org/10.1039/C3CC46685J]. [PMID: 24158240].
[53]
Leulliot, N.; Varani, G. Current topics in RNA-protein recognition: control of specificity and biological function through induced fit and conformational capture. Biochemistry, 2001, 40(27), 7947-7956. [http://dx.doi.org/10.1021/bi010680y]. [PMID: 11434763].
[54]
Draper, D.E. Themes in RNA-protein recognition. J. Mol. Biol., 1999, 293(2), 255-270. [http://dx.doi.org/10.1006/jmbi.1999.2991]. [PMID: 10550207].
[55]
Niu, Y.; Jones, A.J.; Wu, H.; Varani, G.; Cai, J. γ-AApeptides bind to RNA by mimicking RNA-binding proteins. Org. Biomol. Chem., 2011, 9(19), 6604-6609. [http://dx.doi.org/10.1039/c1ob05738c]. [PMID: 21826330].
[56]
Potocky, T.B.; Menon, A.K.; Gellman, S.H. Cytoplasmic and nuclear delivery of a TAT-derived peptide and a β-peptide after endocytic uptake into HeLa cells. J. Biol. Chem., 2003, 278(50), 50188-50194. [http://dx.doi.org/10.1074/jbc.M308719200]. [PMID: 14517218].
[57]
Pepinsky, R.B.; Androphy, E.J.; Corina, K.; Brown, R.; Barsoum, J. Specific inhibition of a human papillomavirus E2 trans-activator by intracellular delivery of its repressor. DNA Cell Biol., 1994, 13(10), 1011-1019. [http://dx.doi.org/10.1089/dna.1994.13.1011]. [PMID: 7945933].
[58]
Niu, Y.; Bai, G.; Wu, H.; Wang, R.E.; Qiao, Q.; Padhee, S.; Buzzeo, R.; Cao, C.; Cai, J. Cellular translocation of a γ-AApeptide mimetic of tat peptide. Mol. Pharm., 2012, 9(5), 1529-1534. [http://dx.doi.org/10.1021/mp300070w]. [PMID: 22413929].
[59]
Umezawa, N.; Gelman, M.A.; Haigis, M.C.; Raines, R.T.; Gellman, S.H. Translocation of a β-peptide across cell membranes. J. Am. Chem. Soc., 2002, 124(3), 368-369. [http://dx.doi.org/10.1021/ja017283v]. [PMID: 11792194].

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy