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PACAP) for the Treatment of Parkinson’S Disease Christopher R Design and Synthesis of Brain Penetrant Glycopeptide Analogues of Pituitary Adenylate Cyclase Activating Peptide (PACAP) for the Treatment of Parkinson’s Disease Christopher R. Apostol,1 Chenxi Liu,1 Lajos Z. Szabò,1 Mitchell J. Bartlett,2,3 Gabriella Molnar,3 Torsten Falk2,3 Michael L. Heien,1 John Streicher,3 and Robin Polt1 Departments of Chemistry & Biochemistry,1 Neurology,2 and Pharmacology,3 The University of Arizona, Tucson, AZ 85721 Abstract Results Conclusions Table 1. Structures of β-Endorphin-Inspired Glycopeptides The pituitary adenylate cyclase activating polypeptide (PACAP) is Table 2. Functional activity of PACAP glycopeptides at PAC1, VPAC1 & VPAC2. • The introduction of a carbohydrate residue into the C-terminus an endogenous neuropeptide closely related to the two vasoactive PAC1 VPAC1 VPAC2 does not have a drastic effect on functional activity. intestinal peptides (VIPs). These peptides are members of the Compound Sequence' EC50' EMAX' EC50' EMAX' EC50' EMAX' secretin family of peptide hormones that activate Class B GPCRs. (nM) (%) (nM) (%) (nM) (%) • Substitution of Methionine in position 17 with Norvaline or PACAP binds and agonizes PAC1, VPAC1, and VPAC2 and inhibits Leucine is tolerated. neuronal apoptosis. It is considered to be neuroprotective in various • Substitution of Threonine 7 with Alanine (CRA3003, CRA3004, PACAP1-27 pathological conditions in the CNS; making it a potential drug Figure 5. Potency values in mouse tail and CRA3005) is detrimental to functional activity and leads to a candidate for treating various neurodegenerative disorders. flick assay following i.v. administration. 0.4,' slight reduction in half-life compared to the other analogues. HSDGIFTDSY SRYRKQMAVK KYLAA 14.8' 0.35'± The glycopeptides were more potent 10 20 0.13,' 100 100 100 However, native PACAP exhibits poor pharmacokinetics as it is VL@CONH ± 1.6 0.16 • CRA series of compounds are relatively more VPAC1 receptor than the unglycosylated controls, 2 0.34 rapidly degraded by several proteases and peptidases; showing low suggesting penetration through the selective compared to the PAC1 receptor and VPAC2 receptor. BBB.3 bioavailability. Furthermore, activation of the VPAC2 receptor can • 2ls98Cell, 2ls98Lact, and 2lsMel exhibited higher selectively for lead to undesired peripheral side effects such as vasodilation and CRA3000 HsDGIFTDSY SRYRKQÑAVK KYLAAV 10 20 25.5 85 1.3 90 241 104 the PAC1 and VPAC1 receptors over the VPAC2 receptor. water retention. Therefore, it is critical that more stable and L@Ser(Glc)@CONH2 • The half-lives of all the PACAP glycopeptides were roughly PAC1/VPAC1-selective agonists be developed, and that they can be CRA3001 HsDGIFTDSY10SRYRKQÑAVK20KYLAAV 54.5 86 4.8 90 654 107 around 15 minutes except for CRA3003, CRA3004, and targeted toward the CNS. One strategy that has not been Glycosylation and Structural Modifications of PACAP: @Ser(Glc)@CONH2 CRA3005, which exhibited half-life values closer to 10 minutes. Improving BBB Transport and Receptor Selectivity extensively explored in the context of PACAP agonists is CRA3002 HsDGIFTDSY10SRYRKQÑAVK20KYLAAL >250 @79 5.9 93 >2500 @95 glycosylation. In other contexts, glycosylation of peptides has been PACAP1-27 Glycosylated PACAP1-27 @Ser(Glc)@L@CONH2 Message Message shown to improve stability, enhance their original biological Glycosylation Carbohydrate Future Directions A CRA3003 HsDGIFADSY10SRYRKQÑAVK20KYLAAV activities, and modulate their ability to cross cellular barriers like the >250 @71 78.8 93 >2500 @42 Address Address L@Ser(Glc)@CONH2 • N-acylation of the N-terminus will be explored to improve half-life. BBB. To this end, we have designed and synthesized several CRA3004 HsDGIFADSY SRYRKQÑAVK KYLAAV Poor Pharmacokinetic Profile Enhanced Stability 10 20 • Amino acid substitutions will be performed in positions 4 and 5. PACAP glycopeptides containing C-terminal serine glycosides and Limited BBB permeability Imrpoved BBB Penetration @Ser(Glc)@CONH NC NC 1366 85 NC NC 5,6 Increased Bioavailability 2 This region may be to be involved with receptor selectivity. additional amino acid substitutions. These glycopeptides were Low Bioavailability evaluated for their ability to stimulate cAMP production in vitro using CRA3005 HsDGIFADSY10SRYRKQÑAVK20KYLAAV • Flexible amino acids or amino acid-like linkers will be @Ser(Glc)@L@CONH NC NC 1623 78 NC NC individual CHO cell lines expressing PAC1, VPAC1, and VPAC2 2 placed in position 4. Carbohydrate Carbohydrate receptors. A select number of the examined glycopeptides exhibited HSDGIFTDSY SRYRKQLAVK KYLAAV • Amino acids with alkyl side chains of varying steric bulk 2ls98Cell 10 20 d8 0.84 92 0.52 93 55.6 91 L@Ser(Cell)@CONH2 will be placed in position 5. the desired pharmacological profiles. These compounds will be B Message Carbohydrate used as leads to further optimize their receptor selectivity, stability, HSDGIFTDSY SRYRKQLAV K KYLAAV • Simultaneous substitution at positions 4 and 5 Address 2ls98Lact 10 d8 20 0.72 93 0.45 101 193 100 and transport properties in vivo. d8L@Ser(Lact)@CONH2 containing "-helix and β-turn inducing motifs will be Message Message explored. Background: Advantages of Glycosylation and Applications in PAC1 HSDGIFTDSY SRYRKQLAVK KYLAAVL@ VPAC1/VPAC2 2ls98Mel 10 20 0.57 99 0.55 102 9.4 86 Opioid Peptides and Angiotensin PAC1R Actvitation: VPAC1R/VPAC2R Activation: Ser(Mel)@CONH2 • Analogues containing extended C-termini will be explored to Neuroprotection Cytokine and Chemokine Activation (VPAC1) V P A C 1 Monosaccharide Disaccharide Neuron Repair V P A C 2 Message Message Message c A M P . S t i m u l a t i o n . i n . P A C 1 ! C H O regain PAC1 receptor selectivity n Pro-Inflammatory Effects (VPAC1) n 1 2 5 P A C A P 1 ! 2 7 1 2 5 o 1 2 5 o i i P A C A P 1 ! 2 7 t t Vasodilation(VPAC2) P A C A P 1 ! 2 7 a a 1 0 0 l 2 l s 9 8 C E l l l n 1 0 0 u 1 0 0 u 2 l s 9 8 C E l l o Water Retention (VPAC2) i C R A 3 0 0 0 Address t m 2 L s 9 8 L a c t m 7 5 Address Address i i a t l 7 5 t 2 L s 9 8 L a c t 7 5 u C R A 3 0 0 1 S S 7 2 L s 9 8 M E l 7 5 0 m P P i 2 L s 9 8 M E l t 5 0 References C R A 3 0 0 2 5 0 M M Koff << Kon Koff > Kon Koff >> Kon S 2 5 . A Figure 4. A. Native PACAP is rapidly degraded in vivo and exhibits limited BBB A P c c 7 2 5 7 0 M 2 5 x x a A Message Monosaccharide Message Disaccharide a Message penetration. Glycosylation should effectively address these concerns. B. Another c . ! 2 5 M 0 M 7 0 7 f f % o o 1. Mabrouk, O. S., Falk, T., Sherman, S. J., Kennedy, R. T. & Polt, R. CNS penetration of the opioid glycopeptide 7 7 ! 5 0 ! 2 5 ! 2 5 % aspect of the PACAP glycopeptide design of is shifting selectivity towards the PAC1 % ! 1 2 ! 1 1 ! 1 0 ! 9 ! 8 ! 7 ! 6 ! 1 1 ! 1 0 ! 9 ! 8 ! 7 ! 6 ! 5 ! 1 1 ! 1 0 ! 9 ! 8 ! 7 ! 6 ! 5 MMP-2200: A microdialysis study. Neurosci. Lett. 531, 99–103 (2012). Address Address Address 4 receptor to reduce side effects mediated through the VPA1 and VPAC2 receptors. L o g [ D r u g ] , M L o g [ D r u g ] , 7 M L o g [ D r u g ] , 7 M c A M P . S t i m u l a t i o n . i n . P A C 1 ! C H O V P A C 1 2. Bartlett, M.J., Liu, C., Smith, C.L., Jones, E.M., Szabò, L.Z., Hanrahan, D.H., Falk, T., Lonhilas, J.P., Heien, V P A C 2 n 1 2 5 1 2 5 n 1 0 0 o M.L., Hay, M., Polt, R. Angiotensin1-7 glycopeptide derivatives act as brain-penetrant hormones that promote o i P A C A P 1 ! 2 7 P A C A P 1 ! 2 7 i t P A C A P 1 ! 2 7 t Materials and Methods n a a l 1 0 0 1 0 0 l o 7 5 i u C R A 3 0 0 0 u cognitive performance. Unpublished manuscript. C R A 3 0 0 3 C R A 3 0 0 0 t a m m l i i t 7 5 7 5 C R A 3 0 0 1 t u C R A 3 0 0 4 5 0 C R A 3 0 0 1 S S 7 7 m i P P R= Peracetylated t C R A 3 0 0 2 C R A 3 0 0 5 C R A 3 0 0 2 5 0 5 0 2 5 S M M . A A Carbohydrate P c c 3. Li, Y., St. Louis, L., Knapp, B. I., Muthu, D., Anglin, B., Giuvelis, D., Bidlack, J. M., Bilsky, E. J. & Polt, R. Can 7 7 1. 2% DBU 2% M 2 5 2 5 0 x x A a a c O . Piperidine in DMF M M amphipathic helices influence the CNS antinociceptive activity of glycopeptides related to ??-endorphin? J. Med. 0 0 ! 2 5 7 7 f % f o o 7 2. DMF wash (x5) 7 ! 2 5 ! 2 5 ! 5 0 Chem. 57, 2237–2246 (2014). % % RO OH 3. Fmoc-AA, HOBt, ! 1 2 ! 1 1 ! 1 0 ! 9 ! 8 ! 7 ! 6 ! 1 1 ! 1 0 ! 9 ! 8 ! 7 ! 6 ! 5 ! 1 1 ! 1 0 ! 9 ! 8 ! 7 ! 6 ! 5 1.
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