Abstract
Specific peptide molecules classified as hormones, neuropeptides and cytokines are involved in intercellular signaling regulating various physiological processes in all organs and tissues. This justifies the peptidergic signaling as an attractive pharmacological target. Recently, a protein mimetic of a peptide hormone has been identified in Escherichia coli suggesting the potential use of specific bacterial proteins as a new type of peptide-like drugs. We review the scientific rational and technological approaches leading to the identification of the E. coli caseinolytic protease B (ClpB) homologue protein as a conformational mimetic of α-melanocyte-stimulating hormone (α-MSH), a melanocortin peptide critically involved in the regulation of energy homeostasis in humans and animals. Theoretical and experimental backgrounds for the validation of bacterial ClpB as a potential drug are discussed based on the known E. coli ClpB amino acid sequence homology with α-MSH. Using in silico analysis, we show that other protein sources containing similar to E. coli ClpB α-MSH-like epitopes with potential biological activity may exist in Enterobacteriaceae and in some Brassicaceae. Thus, the original approach leading to the identification of E. coli ClpB as an α-MSH mimetic protein can be applied for the identification of mimetic proteins of other peptide hormones and development of a new type of peptide-like protein-based drugs.
Keywords: Peptide hormone, neuropeptide, melanocortin, proteomics, energy metabolism, gut microbiota, molecular mimicry.
[1]
Kastin, A.J.; Pan, W. Concepts for biologically active peptides. Curr. Pharm. Des., 2010, 16(30), 3390-3400.
[2]
Scott, R.D. Glucagon-like peptide-1 receptor agonists for type 2 diabetes: A clinical update of safety and efficacy. Curr. Diabetes Rev., 2016, 12(4), 403-413.
[4]
Schwartz, M.W.; Woods, S.C.; Porte, D., Jr; Seeley, R.J.; Baskin, D.G. Central nervous system control of food intake. Nature, 2000, 404(6778), 661-671.
[5]
Cone, R.D. Studies on the physiological functions of the melanocortin system. Endocr. Rev., 2006, 27(7), 736-749.
[6]
Anderson, E.J.P.; Çakir, I.; Carrington, S.J.; Cone, R.D.; Ghamari-Langroudi, M.; Gillyard, T.; Gimenez, L.E.; Litt, M.J. 60 years of POMC: Regulation of feeding and energy homeostasis by α-MSH. J. Mol. Endocrinol., 2016, 56(4), T157-T174.
[7]
Yaswen, L.; Diehl, N.; Brennan, M.B.; Hochgeschwender, U. Obesity in the mouse model of pro-opiomelanocortin deficiency responds to peripheral melanocortin. Nat. Med., 1999, 5(9), 1066-1070.
[8]
Krude, H.; Biebermann, H.; Luck, W.; Horn, R.; Brabant, G.; Gruters, A. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat. Genet., 1998, 19(2), 155-157.
[9]
Huszar, D.; Lynch, C.A.; Fairchild-Huntress, V.; Dunmore, J.H.; Fang, Q.; Berkemeier, L.R.; Gu, W.; Kesterson, R.A.; Boston, B.A.; Cone, R.D.; Smith, F.J.; Campfield, L.A.; Burn, P.; Lee, F. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell, 1997, 88(1), 131-141.
[10]
Farooqi, I.S.; Keogh, J.M.; Yeo, G.S.H.; Lank, E.J.; Cheetham, T.; O’Rahilly, S. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N. Engl. J. Med., 2003, 348(12), 1085-1095.
[11]
Chen, K.Y.; Muniyappa, R.; Abel, B.S.; Mullins, K.P.; Staker, P.; Brychta, R.J.; Zhao, X.; Ring, M.; Psota, T.L.; Cone, R.D.; Panaro, B.L.; Gottesdiener, K.M.; Van der Ploeg, L.H.; Reitman, M.L.; Skarulis, M.C. RM-493, a melanocortin-4 receptor (MC4R) agonist, increases resting energy expenditure in obese individuals. J. Clin. Endocrinol. Metab., 2015, 100(4), 1639-1645.
[12]
Kühnen, P.; Clément, K.; Wiegand, S.; Blankenstein, O.; Gottesdiener, K.; Martini, L.L.; Mai, K.; Blume-Peytavi, U.; Grüters, A.; Krude, H. Proopiomelanocortin deficiency treated with a melanocortin-4 receptor agonist. N. Engl. J. Med., 2016, 375(3), 240-246.
[13]
Samuelsson, A-M.S.; Mullier, A.; Maicas, N.; Oosterhuis, N.R.; Eun Bae, S.; Novoselova, T.V.; Chan, L.F.; Pombo, J.M.; Taylor, P.D.; Joles, J.A.; Coen, C.W.; Balthasar, N.; Poston, L. Central role for melanocortin-4 receptors in off-spring hypertension arising from maternal obesity. Proc. Natl. Acad. Sci. USA, 2016, 113(43), 12298-12303.
[14]
Berglund, E.D.; Liu, T.; Kong, X.; Sohn, J-W.; Vong, L.; Deng, Z.; Lee, C.E.; Lee, S.; Williams, K.W.; Olson, D.P.; Scherer, P.E.; Lowell, B.B.; Elmquist, J.K. Melanocortin 4 receptors in autonomic neurons regulate thermogenesis and glycemia. Nat. Neurosci., 2014, 17(7), 911-913.
[15]
Panaro, Brandon.L.; Tough, Iain.R.; Engelstoft, Maja.S.; Matthews, Robert.T.; Digby, Gregory.J.; Møller, Cathrine.L. Svendsen, B.; Gribble, F.; Reimann, F.; Holst, Jens J.; Holst, B.; Schwartz, Thue W.; Cox, Helen M.; Cone, Roger D. The melanocortin-4 receptor is expressed in enter-oendocrine L cells and regulates the release of peptide YY and glucagon-like peptide 1 in vivo. Cell Metab., 2014, 20(6), 1018-1029.
[16]
Fetissov, S.O.; Hallman, J.; Oreland, L.; Af Klinteberg, B.; Grenbäck, E.; Hulting, A.L.; Hökfelt, T. Autoantibodies against alpha-MSH, ACTH, and LHRH in anorexia and bulimia nervosa patients. Proc. Natl. Acad. Sci. USA, 2002, 99(26), 17155-17160.
[17]
Fetissov, S.O.; Hamze Sinno, M.; Coëffier, M.; Bole-Feysot, C.; Ducrotté, P.; Hökfelt, T.; Déchelotte, P. Autoantibodies against appetite-regulating peptide hormones and neuropeptides: Putative modulation by gut microflora. Nutrition, 2008, 24(4), 348-359.
[18]
Fetissov, S.O.; Harro, J.; Jaanisk, M.; Järv, A.; Podar, I.; Allik, J.; Nilsson, I.; Sakthivel, P.; Lefvert, A.K.; Hökfelt, T. Autoantibodies against neuropeptides are associated with psychological traits in eating disorders. Proc. Natl. Acad. Sci. USA, 2005, 102(41), 14865-14870.
[19]
Oldstone, M.B. Molecular mimicry and immune-mediated diseases. FASEB J., 1998, 12(13), 1255-1265.
[20]
Fetissov, S.O. Autoimmune component in anorexia and bulimia nervosa. In: Neuropsychiatric Disorders and Infection; Fatemi, S.H., Ed.; Taylor & Francis Books Ltd: London, 2004; pp. 253-262.
[21]
Winter, S.E.; Winter, M.G.; Xavier, M.N.; Thiennimitr, P.; Poon, V.; Keestra, A.M.; Laughlin, R.C.; Gomez, G.; Wu, J.; Lawhon, S.D.; Popova, I.E.; Parikh, S.J.; Adams, L.G.; Tsolis, R.M.; Stewart, V.J.; Bäumler, A.J. Host-derived nitrate boosts growth of E. coli in the inflamed gut. Science, 2013, 339(6120), 708-711.
[22]
Sassone-Corsi, M.; Nuccio, S-P.; Liu, H.; Hernandez, D.; Vu, C.T.; Takahashi, A.A.; Edwards, R.A.; Raffatellu, M. Microcins mediate competition among Enterobacteriaceae in the inflamed gut. Nature, 2016, 540(7632), 280-283.
[23]
Tennoune, N.; Chan, P.; Breton, J.; Legrand, R.; Chabane, Y.N.; Akkermann, K.; Jarv, A.; Ouelaa, W.; Takagi, K.; Ghouzali, I.; François, M.; Lucas, N.; Bole-Feysot, C.; Pestel-Caron, M.; do Rego, J.C.; Vaudry, D.; Harro, J.; Dé, E.; Déchelotte, P.; Fetissov, S.O. Bacterial ClpB heat-shock protein, an antigen-mimetic of the anorexigenic peptide [alpha]-MSH, at the origin of eating disorders. Transl. Psychiatry, 2014, 4, e458.
[24]
Hamze Sinno, M.; Do Rego, J.C.; Coëffier, M.; Bole-Feysot, C.; Ducrotte, P.; Gilbert, D.; Tron, F.; Costentin, J.; Hökfelt, T.; Déchelotte, P.; Fetissov, S.O. Regulation of feeding and anxiety by α-MSH reactive autoantibodies. Psychoneuroendocrinology, 2009, 34(1), 140-149.
[25]
Karaiskos, D.; Mavragani, C.P.; Sinno, M.H.; Déchelotte, P.; Zintzaras, E.; Skopouli, F.N.; Fetissov, S.O.; Moutsopoulos, H.M. Psychopathological and personality features in primary Sjogren’s syndrome--associations with autoantibodies to neuropeptides. Rheumatology, 2010, 49(9), 1762-1769.
[26]
Takagi, K.; Legrand, R.; Asakawa, A.; Amitani, H.; François, M.; Tennoune, N.; Coëffier, M.; Claeyssens, S.; do Rego, J-C.; Déchelotte, P.; Inui, A.; Fetissov, S.O. Anti-ghrelin immunoglobulins modulate ghrelin stability and its orexigenic effect in obese mice and humans. Nat. Commun., 2013, 4, 2685.
[27]
Lucas, N.; Legrand, R.; Ouelaa, W.; Breton, J.; Tennoune, N.; Bole-Feysot, C.; Déchelotte, P.; Fetissov, S.O. Effects of rabbit anti-α-melanocyte-stimulating hormone (α -MSH) immunoglobulins on α-MSH signaling related to food intake control. Neuropeptides, 2014, 48, 21-27.
[28]
Lucas, N.; Legrand, R.; Bôle-Feysot, C.; Breton, J.; Coëffier, M.; Akkermann, K.; Järv, A.; Harro, J.; Déchelotte, P.; Fetissov, S.O. Immunoglobulin G modulation of the melanocortin 4 receptor signaling in obesity and eating disorders. Transl. Psychiatry, 2019, 9(1), 87.
[29]
Harris, J.I.; Lerner, A.B. Amino-acid sequence of the alpha-melanocyte-stimulating hormone. Nature, 1957, 179(4574), 1346-1347.
[30]
Hruby, V.J.; Cai, M.; Cain, J.; Nyberg, J.; Trivedi, D. Design of novel melanocortin receptor ligands: Multiple receptors, complex pharmacology, the challenge. Eur. J. Pharmacol., 2011, 660(1), 88-93.
[31]
Holder, J.R.; Haskell-Luevano, C. Melanocortin ligands: 30 years of structure-activity relationship (SAR) studies. Med. Res. Rev., 2004, 24(3), 325-356.
[32]
Haskell-Luevano, C.; Holder, J.R.; Monck, E.K.; Bauzo, R.M. Characterization of melanocortin NDP-MSH agonist peptide fragments at the mouse central and peripheral melanocortin receptors. J. Med. Chem., 2001, 44(13), 2247-2252.
[33]
Schiöth, H.B.; Mutulis, F.; Muceniece, R.; Prusis, P.; Wik-berg, J.E.S. Selective properties of C- and N-terminals and core residues of the melanocyte-stimulating hormone on binding to the human melanocortin receptor subtypes. Eur. J. Pharmacol., 1998, 349(2-3), 359-366.
[34]
Hruby, V.J.; Wilkes, B.C.; Hadley, M.E.; Al-Obeidi, F.; Sawyer, T.K.; Staples, D.J.; DeVaux, A.; Dym, O.; Ca-strucci, A.M.; Hintz, M.F.; Riehm, J.P.; Rao, K.R. α-Melanotropin: The minimal active sequence in the frog skin bioassay. J. Med. Chem., 1987, 30, 2126-2130.
[35]
Todorovic, A.; Ericson, M.D.; Palusak, R.D.; Sorensen, N.B.; Wood, M.S.; Xiang, Z.; Haskell-Luevano, C. Compara-tive functional alanine positional scanning of the α-melanocyte stimulating hormone and NDP-melanocyte stimulating hormone demonstrates differential structure-activity relationships at the mouse melanocortin receptors. ACS Chem. Neurosci., 2016, (7), 984-994.
[36]
Prabhu, N.V.; Perkyns, J.S.; Pettitt, B.M.; Hruby, V.J. Structure and dynamics of α-MSH using DRISM integral equation theory and stochastic dynamics. Biopolymers, 1999, 50(3), 255-272.
[37]
Donald, J.E.; Kulp, D.W.; DeGrado, W.F. Salt bridges: Geometrically specific, designable interactions. Proteins, 2011, 79(3), 898-915.
[38]
Li, S-Z.; Lee, J-H.; Lee, W.; Yoon, C-J.; Baik, J-H.; Lim, S-K. Type I β-turn conformation is important for biological activity of the melanocyte-stimulating hormone analogues. Eur. J. Biochem., 1999, 265(1), 430-440.
[39]
Sawyer, T.K.; Sanfilippo, P.J.; Hruby, V.J.; Engel, M.H.; Heward, C.B.; Burnett, J.B.; Hadley, M.E. 4-Norleucine, 7-D-phenylalanine-alpha-melanocyte-stimulating hormone: A highly potent alpha-melanotropin with ultralong biological activity. Proc. Natl. Acad. Sci. USA, 1980, 77(10), 5754-5758.
[40]
Liang , Zeng Y.; Hansen, M. H.; Mark, L. H.; Robert, A. G.; Paul, J. E.; JeAnne, H.; David, F.; Patrick, E.; Dave, S.; Lianshan, Z.; Saba, H.; Steven, D. K.; Richard, D. D.; John, P. M., Structure-activity relationships of beta-MSH derived melanocortin-4 receptor peptide agonists. Curr. Top. Med. Chem., 2007, 7(11), 1052-1067.
[41]
Cai, M.; Hruby, V.J. Design of cyclized selective melanotropins. Peptide Sci, 2016, 106(6), 876-883.
[42]
Mayorov, A.V.; Cai, M.; Palmer, E.S.; Tanaka, D.K.; Cain, J.P.; Dedek, M.M.; Tan, B.; Trivedi, D.; Hruby, V.J. Cyclic lactam hybrid α-MSH/Agouti-related protein (AGRP) analogues with nanomolar range binding affinities at the human melanocortin receptors. Bioorg. Chem. Lett, 2011, 21(10), 3099-3102.
[43]
Wilczynski, A.M.; Joseph, C.G.; Haskell-Luevano, C. Current trends in the structure-activity relationship studies of the endogenous agouti-related protein (AGRP) melanocortin receptor antagonist. Med. Res. Rev., 2005, 25(5), 545-556.
[44]
Ericson, M.D.; Schnell, S.M.; Freeman, K.T.; Haskell-Luevano, C. A fragment of the Escherichia coli ClpB heat-shock protein is a micromolar melanocortin 1 receptor agonist. Bioorg. Chem. Lett, 2015, 25(22), 5306-5308.
[45]
Mogk, A.; Schlieker, C.; Strub, C.; Rist, W.; Weibezahn, J.; Bukau, B. Roles of individual domains and conserved motifs of the AAA+ chaperone CLPB in oligomerization, ATP hydrolysis, and chaperone activity. J. Biol. Chem., 2003, 278(20), 17615-17624.
[46]
Lee, S.; Sowa, M.E.; Watanabe, Y.H.; Sigler, P.B.; Chiu, W.; Yoshida, M.; Tsai, F.T. The structure of ClpB: A molecular chaperone that rescues proteins from an aggregated state. Cell, 2003, 115(2), 229-240.
[47]
Kupper, M.; Gupta, S.K.; Feldhaar, H.; Gross, R. Versatile roles of the chaperonin GroEL in microorganism-insect interactions. FEMS Microbiol. Lett., 2014, 353(1), 1-10.
[48]
Dalmasso, G.; Charrier-Hisamuddin, L.; Thu Nguyen, H.T.; Yan, Y.; Sitaraman, S.; Merlin, D. PepT1-mediated tripeptide kpv uptake reduces intestinal inflammation. Gastroenterology, 2008, 134(1), 166-178.
[49]
Valnet, J. Traitement des maladies par les legumes, les frouits et les cereales, 9th ed; Maloine SA: Paris, 1985, p. 509.
[50]
Aiso, I.; Inoue, H.; Seiyama, Y.; Kuwano, T. Compared with the intake of commercial vegetable juice, the intake of fresh fruit and komatsuna (Brassica rapa L. var. perviridis) juice mixture reduces serum cholesterol in middle-aged men: A randomized controlled pilot study. Lipids Health Dis., 2014, 13(1), 102.
[51]
Azhar, S. Lucas, N.; Breton, J.; do Rego, J. C.; Déchelotte, P.; Fetissov, S. O.; Lambert, G.; Legrand, R. In Influence d'une protéine mimétique de l'alpha-melanocyte stimulating hormone (α-MSH), la caseinolytic peptidase B (ClpB) sur le comportement alimentaire et la croissance des souris obèses, Journées Francophones de Nutrition, Montpellier, France, 30 Nov - 2 Dec; Montpellier, France, 2016.
[52]
Chen, A.S.; Metzger, J.M.; Trumbauer, M.E.; Guan, X.M.; Yu, H.; Frazier, E.G.; Marsh, D.J.; Forrest, M.J. Go-pal-Truter, S.; Fisher, J.; Camacho, R. E.; Strack, A. M.; Mellin, T. N.; MacIntyre, D. E.; Chen, H. Y.; Van der Ploeg, L. H. Role of the melanocortin-4 receptor in metabolic rate and food intake in mice. Transgenic Res., 2000, 9(2), 145-154.
[53]
Trivedi, P.; Jiang, M.; Tamvakopoulos, C.C.; Shen, X.; Yu, H.; Mock, S.; Fenyk-Melody, J.; Van der Ploeg, L.H.T.; Guan, X-M. Exploring the site of anorectic action of peripherally administered synthetic melanocortin peptide MT-II in rats. Brain Res., 2003, 977(2), 221-230.
[54]
Kievit, P.; Halem, H.; Marks, D.L.; Dong, J.Z.; Glavas, M.M.; Sinnayah, P.; Pranger, L.; Cowley, M.A.; Grove, K.L.; Culler, M.D. Chronic treatment with a melanocortin-4 receptor agonist causes weight loss, reduces insulin resistance, and improves cardiovascular function in diet-induced obese rhesus macaques. Diabetes, 2013, 62(2), 490-497.
[55]
Fetissov, S.O. Role of the gut microbiota in host appetite control: Bacterial growth to animal feeding behaviour. Nat. Rev. Endocrinol., 2017, 13, 11-25.
[56]
Breton, J.; Tennoune, N.; Lucas, N.; François, M.; Legrand, R.; Jacquemot, J.; Goichon, A.; Guérin, C.; Peltier, J.; Pestel-Caron, M.; Chan, P.; Vaudry, D.; do Rego, J.C.; Liénard, F.; Pénicaud, J.; Fioramonti, X.; Ebenezer, I.S.; Hökfelt, T.; Déchelotte, P.; Fetissov, S.O. Gut commensal E.coli proteins activate host satiety pathways following nutrient-induced bacterial growth. Cell Metab., 2016, 23, 1-11.
[57]
Breton, J.; Legrand, R.; Akkermann, K.; Järv, A.; Harro, J.; Déchelotte, P.; Fetissov, S.O. Elevated plasma concentrations of bacterial ClpB protein in patients with eating disorders. Int. J. Eat. Disord., 2016, 49(8), 805-808.
[58]
Fetissov, S.; Lucas, N.; Legrand, R. Ghrelin-reactive immunoglobulins in conditions of altered appetite and energy balance. Front. Endocrinol., 2017, 8(10)
[http://dx.doi.org/10.3389/fendo.2017.00010]
[http://dx.doi.org/10.3389/fendo.2017.00010]
[59]
Sebriakova, M.; Little, J.A. A method for the determination of plasma insulin antibodies and its application in normal and diabetic subjects. Diabetes, 1973, 22(1), 30-40.
Related Journals
Current Pharmaceutical Design
Current Topics in Medicinal Chemistry
Current Respiratory Medicine Reviews
Infectious Disorders - Drug Targets
Endocrine, Metabolic & Immune Disorders - Drug Targets
Anti-Infective Agents
Coronaviruses
Recent Advances in Inflammation & Allergy Drug Discovery
Current Probiotics
Article Metrics
53
2