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1.  The Mammalian Neuronal Sodium Channel Blocker μ-Conotoxin BuIIIB has a Structured N-terminus that Influences Potency 
ACS chemical biology  2013;8(6):1344-1351.
Among the μ-conotoxins that block vertebrate voltage-gated sodium channels (VGSCs), some have been shown to be potent analgesics following systemic administration in mice. We have determined the solution structure of a new representative of this family, μ-BuIIIB, and established its disulfide connectivities by direct mass spectrometric collision induced dissociation fragmentation of the peptide with disulfides intact. The major oxidative folding product adopts a 1-4/2-5/3-6 pattern with the following disulfide bridges: Cys5-Cys17, Cys6-Cys23 and Cys13-Cys24. The solution structure reveals that the unique N-terminal extension in μ-BuIIIB, which is also present in μ-BuIIIA and μ-BuIIIC but absent in other μ-conotoxins, forms part of a short α-helix encompassing Glu3 to Asn8. This helix is packed against the rest of the toxin and stabilized by the Cys5-Cys17 and Cys6-Cys23 disulfide bonds. As such, the side chain of Val1 is located close to the aromatic rings of Trp16 and His20, which are located on the canonical helix that displays several residues found to be essential for VGSC blockade in related μ-conotoxins. Mutations of residues 2 and 3 in the N-terminal extension enhanced the potency of μ-BuIIIB for NaV1.3. One analog, [d-Ala2]BuIIIB, showed a 40-fold increase, making it the most potent peptide blocker of this channel characterized to date and thus a useful new tool with which to characterize this channel. Based on previous results for related μ-conotoxins, the dramatic effects of mutations at the N-terminus were unanticipated, and suggest that further gains in potency might be achieved by additional modifications of this region.
doi:10.1021/cb300674x
PMCID: PMC4201638  PMID: 23557677
2.  Expression and Functional Characterization of Membrane-Integrated Mammalian Corticotropin Releasing Factor Receptors 1 and 2 in Escherichia coli 
PLoS ONE  2014;9(1):e84013.
Corticotropin-Releasing Factor Receptors (CRFRs) are class B1 G-protein-coupled receptors, which bind peptides of the corticotropin releasing factor family and are key mediators in the stress response. In order to dissect the receptors' binding specificity and enable structural studies, full-length human CRFR1α and mouse CRFR2β as well as fragments lacking the N-terminal extracellular domain, were overproduced in E. coli. The characteristics of different CRFR2β -PhoA gene fusion products expressed in bacteria were found to be in agreement with the predicted ones in the hepta-helical membrane topology model. Recombinant histidine-tagged CRFR1α and CRFR2β expression levels and bacterial subcellular localization were evaluated by cell fractionation and Western blot analysis. Protein expression parameters were assessed, including the influence of E. coli bacterial hosts, culture media and the impact of either PelB or DsbA signal peptide. In general, the large majority of receptor proteins became inserted in the bacterial membrane. Across all experimental conditions significantly more CRFR2β product was obtained in comparison to CRFR1α. Following a detergent screen analysis, bacterial membranes containing CRFR1α and CRFR2β were best solubilized with the zwitterionic detergent FC-14. Binding of different peptide ligands to CRFR1α and CRFR2β membrane fractions were similar, in part, to the complex pharmacology observed in eukaryotic cells. We suggest that our E. coli expression system producing functional CRFRs will be useful for large-scale expression of these receptors for structural studies.
doi:10.1371/journal.pone.0084013
PMCID: PMC3894963  PMID: 24465390
3.  Anxiolytic-Like Effects of Antisauvagine-30 in Mice Are Not Mediated by CRF2 Receptors 
PLoS ONE  2013;8(8):e63942.
The role of brain corticotropin-releasing factor type 2 (CRF2) receptors in behavioral stress responses remains controversial. Conflicting findings suggest pro-stress, anti-stress or no effects of impeding CRF2 signaling. Previous studies have used antisauvagine-30 as a selective CRF2 antagonist. The present study tested the hypotheses that 1) potential anxiolytic-like actions of intracerebroventricular (i.c.v.) administration of antisauvagine-30 also are present in mice lacking CRF2 receptors and 2) potential anxiolytic-like effects of antisauvagine-30 are not shared by the more selective CRF2 antagonist astressin2-B. Cannulated, male CRF2 receptor knockout (n = 22) and wildtype littermate mice (n = 21) backcrossed onto a C57BL/6J genetic background were tested in the marble burying, elevated plus-maze, and shock-induced freezing tests following pretreatment (i.c.v.) with vehicle, antisauvagine-30 or astressin2-B. Antisauvagine-30 reduced shock-induced freezing equally in wildtype and CRF2 knockout mice. In contrast, neither astressin2-B nor CRF2 genotype influenced shock-induced freezing. Neither CRF antagonist nor CRF2 genotype influenced anxiety-like behavior in the plus-maze or marble burying tests. A literature review showed that the typical antisauvagine-30 concentration infused in previous intracranial studies (∼1 mM) was 3 orders greater than its IC50 to block CRF1-mediated cAMP responses and 4 orders greater than its binding constants (Kd, Ki) for CRF1 receptors. Thus, increasing, previously used doses of antisauvagine-30 also exert non-CRF2-mediated effects, perhaps via CRF1. The results do not support the hypothesis that brain CRF2 receptors tonically promote anxiogenic-like behavior. Utilization of CRF2 antagonists, such as astressin2-B, at doses that are more subtype-selective, can better clarify the significance of brain CRF2 systems in stress-related behavior.
doi:10.1371/journal.pone.0063942
PMCID: PMC3756045  PMID: 24015170
4.  Novel, Potent and Radio-Iodinatable Somatostatin Receptor 1 (sst1) Selective Analogues 
Journal of medicinal chemistry  2009;52(9):2733-2746.
The proposed sst1 pharmacophore1 derived from the NMR structures of a family of mono- and dicyclic undecamers was used to design octa-, hepta- and hexamers with high affinity and selectivity for the somatostatin sst1 receptor. These compounds were tested for their in vitro binding properties to all five somatostatin (SRIF) receptors using receptor autoradiography; those with high SRIF receptor subtype 1 (sst1) affinity and selectivity were shown to be agonists when tested functionally in a luciferase reporter gene assay. Des-AA1,4-6,10,12,13-[DTyr2,DAgl(NMe,2naphthoyl)8,IAmp9]-SRIF-Thr-NH2 (25) was radio-iodinated (125I-25) and specifically labeled sst1-expressing cells and tissues. 3D NMR structures were calculated for des-AA1,4-6,10,12,13-[DPhe2,DTrp8,IAmp9]-SRIF-Thr-NH2 (16), des-AA1,2,4-6,10,12,13-[DAgl(NMe,2naphthoyl)8,IAmp9]-SRIF-Thr-NH2 (23) and des-AA1,2,4-6,10,12,13-[DAgl(NMe,2naphthoyl)8,IAmp9,Tyr11]-SRIF-NH2 (27) in DMSO. Though the analogues have the sst1 pharmacophore residues at the previously determined distances from each other, the positioning of the aromatic residues in 16, 23 and 27 is different from that described earlier suggesting an induced fit mechanism for sst1 binding of these novel, less constrained sst1-selective family members.
doi:10.1021/jm801314f
PMCID: PMC2779710  PMID: 19351180
somatostatin analogues; radio-iodinatable SRIF analogues; SAR; NMR structures; somatostatin receptor 1 selectivity
5.  Design and in vitro Characterization of Highly Sst2-selective Somatostatin Antagonists Suitable for Radio-Targeting 
Journal of medicinal chemistry  2008;51(13):4030-4037.
Radiolabeled sst2 and sst3 antagonists are better candidates for tumor targeting than agonists with comparable binding characteristics.1 Because the majority of neuroendocrine tumors express sst2, we used the known antagonists Acetyl-pNO2Phe2-c[dCys3-Tyr7-dTrp8-Lys9-Thr10-Cys14]-dTyr15-NH2 (1)2,3 and H-Cpa2-c[dCys3-Tyr7-dTrp8-Lys9-Thr10-Cys14]-2Nal15-NH2 (7)4 as leads for analogues with increased sst2 binding affinity and selectivity. Among the 32 analogues reported here, DOTA-pNO2Phe-c[dCys-Tyr-dAph(Cbm)-Lys-Thr-Cys]-dTyr-NH2 (3) and DOTA-Cpa-c[dCys-Aph(Hor)-dAph(Cbm)-Lys-Thr-Cys]-dTyr-NH2 (31) had the highest sst2 binding affinity and selectivity. All of the analogues tested kept their sst2 antagonistic properties (i.e. did not affect calcium release in vitro and competitively antagonized the agonistic effect of [Tyr3]-octreotide). Moreover, in an immunofluorescence-based internalization assay, the new analogues prevented sst2 internalization induced by the sst2 agonist [Tyr3]-octreotide, without being active by themselves. In conclusion, several analogues (in particular 3, 31 and 32) have outstanding sst2 binding and functional antagonistic properties and, because of their DOTA moiety, are excellent candidates for in vivo targeting of sst2-expressing cancers.
doi:10.1021/jm701618q
PMCID: PMC2789649  PMID: 18543899
6.  Ring Size in Octreotide Amide Modulates Differently Agonist versus Antagonist Binding Affinity and Selectivity 
Journal of medicinal chemistry  2008;51(9):2676-2681.
H-dPhe2-c[Cys3-Phe7-dTrp8-Lys9-Thr10-Cys14]-Thr15-NH2 (1) (a somatostatin agonist) (SRIF numbering) and H-Cpa2-c[dCys3-Tyr7-dTrp8-Lys9-Thr10-Cys14]-Nal15-NH2 (4) (a somatostatin antagonist), are based on the structure of octreotide that binds to three somatostatin receptor subtypes (sst2/3/5) with significant binding affinity. Analogues of 1 and 4 were synthesized with norcysteine (Ncy), homocysteine (Hcy) or dHcy at positions 3 and/or 14. Introducing Ncy at positions 3 and 14 constrains the backbone flexibility, resulting in loss of binding affinity at all ssts. The introduction of Hcy at positions 3 and 14 improved selectivity for sst2 as a result of significant loss of binding affinity at the other ssts. Substitution by dHcy at position 3 in the antagonist scaffold (5), on the other hand, resulted in a significant loss of binding affinity at sst2 and sst3 as compared to the different affinities of the parent compound (4). The 3D NMR structures of the analogues in DMSO are consistent with the observed binding affinities.
doi:10.1021/jm701445q
PMCID: PMC2789646  PMID: 18410083
somatostatin analogues; homocysteine; norcysteine; SAR; NMR structures; somatostatin receptor selectivity
7.  Synthesis of protected norcysteines for SPPS compatible with Fmoc-strategy 
Tetrahedron letters  2007;48(29):5107-5110.
We report the synthesis of racemic Alloc-Ncy(Tmob)-OH, the resolution of its methyl ester, and demonstrate its application to form a norcystine bridge in octreotide-amide using the Fmoc-strategy on solid phase. N-Alloc and S-Tmob protections of norcysteine (Ncy) were found to be a preferred choice for Fmoc-strategy over three other protected norcysteines synthesized i.e. Fmoc-Ncy(tBu)-OH, Alloc-Ncy(tBu)-OH and Alloc-Ncy(Trt)-OH.
doi:10.1016/j.tetlet.2007.05.082
PMCID: PMC2701708  PMID: 19562100
norcysteine; norcystine; SPPS; somatostatin; octreotide
8.  Lactam-stabilized helical analogues of the analgesic μ-conotoxin KIIIA 
Journal of medicinal chemistry  2011;54(21):7558-7566.
μ-Conotoxin KIIIA (μ-KIIIA) blocks mammalian voltage-gated sodium channels (VGSCs) and is a potent analgesic following systemic administration in mice. Previous structure-activity studies of μ-KIIIA identified a helical pharmacophore for VGSC blockade. This suggested a route for designing truncated analogues of μ-KIIIA by incorporating the key residues into an α-helical scaffold. As (i, i+4) lactam bridges constitute a proven approach for stabilizing α-helices, we designed and synthesized six truncated analogues of μ-KIIIA containing single lactam bridges at various locations. The helicity of these lactam analogues was analysed by NMR spectroscopy, and their activities were tested against mammalian VGSC subtypes NaV1.1 through 1.7. Two of the analogues, Ac-cyclo9/13[Asp9,Lys13]KIIIA7–14 and Ac-cyclo9/13[Lys9,Asp13]KIIIA7–14, displayed µM activity against VGSC subtypes NaV1.2 and NaV1.6; importantly, the subtype selectivity profile for these peptides matched that of μ-KIIIA. Our study highlights structure-activity relationships within these helical mimetics and provides a basis for the design of additional truncated peptides as potential analgesics.
doi:10.1021/jm200839a
PMCID: PMC3228837  PMID: 21962108
9.  CRF Induces Intestinal Epithelial Barrier Injury via the Release of Mast Cell Proteases and TNF-α 
PLoS ONE  2012;7(6):e39935.
Background and Aims
Psychological stress is a predisposing factor in the onset and exacerbation of important gastrointestinal diseases including irritable bowel syndrome (IBS) and the inflammatory bowel diseases (IBD). The pathophysiology of stress-induced intestinal disturbances is known to be mediated by corticotropin releasing factor (CRF) but the precise signaling pathways remain poorly understood. Utilizing a porcine ex vivo intestinal model, the aim of this study was to investigate the mechanisms by which CRF mediates intestinal epithelial barrier disturbances.
Methodology
Ileum was harvested from 6–8 week-old pigs, mounted on Ussing Chambers, and exposed to CRF in the presence or absence of various pharmacologic inhibitors of CRF-mediated signaling pathways. Mucosal-to-serosal flux of 4 kDa-FITC dextran (FD4) and transepithelial electrical resistance (TER) were recorded as indices of intestinal epithelial barrier function.
Results
Exposure of porcine ileum to 0.05–0.5 µM CRF increased (p<0.05) paracellular flux compared with vehicle controls. CRF treatment had no deleterious effects on ileal TER. The effects of CRF on FD4 flux were inhibited with pre-treatment of tissue with the non-selective CRF1/2 receptor antagonist Astressin B and the mast cell stabilizer sodium cromolyn (10−4 M). Furthermore, anti-TNF-α neutralizing antibody (p<0.01), protease inhibitors (p<0.01) and the neural blocker tetrodotoxin (TTX) inhibited CRF-mediated intestinal barrier dysfunction.
Conclusion
These data demonstrate that CRF triggers increases in intestinal paracellular permeability via mast cell dependent release of TNF-α and proteases. Furthermore, CRF-mast cell signaling pathways and increases in intestinal permeability require critical input from the enteric nervous system. Therefore, blocking the deleterious effects of CRF may address the enteric signaling of mast cell degranulation, TNFα release, and protease secretion, hallmarks of IBS and IBD.
doi:10.1371/journal.pone.0039935
PMCID: PMC3386952  PMID: 22768175
10.  Novel dimeric DOTA-coupled peptidic Y1-receptor antagonists for targeting of neuropeptide Y receptor-expressing cancers 
EJNMMI Research  2011;1:21.
Background
Several peptide hormone receptors were identified that are specifically over-expressed on the cell surface of certain human tumors. For example, high incidence and density of the Y1 subtype of neuropeptide Y (NPY) receptors are found in breast tumors. Recently, we demonstrated that the use of potent radiolabeled somatostatin or bombesin receptor antagonists considerably improved the sensitivity of in vivo imaging when compared to agonists. We report here on the first DOTA-coupled peptidic Y1 receptor affine dimer antagonists.
Methods
Based on a Y1 affine dimeric peptide scaffold previously reported to competitively antagonize NPY-mediated processes, we have developed new dimeric DOTA-coupled Y1 receptor affine antagonists for scintigraphy and radiotherapy. These dimeric peptides were tested for their specific binding to Y1 expressed in SK-N-MC cells and Y2 expressed in SH-SY5Y as well as for their ability to mediate cAMP production in SK-N-MC cells.
Results
Introduction of two DOTA moieties at the N-termini of the dimeric NPY analogs as well as the double Asn29 replacement by Dpr(DOTA) or Lys(DOTA) (6 and 10) moiety dramatically reduced binding affinity. However, asymmetric introduction of the DOTA moiety in one segment of the peptidic heterodimer (8 and 11) resulted in suitable antagonists for receptor targeting with high binding affinity for Y1. All compounds were devoid of Y2 binding affinity.
Conclusions
The design and the in vitro characterization of the first DOTA-coupled dimeric NPY receptor antagonist with high affinity and selectivity for Y1 over Y2 are described. This compound may be an excellent candidate for the imaging of Y1-positive tumors and their treatment.
doi:10.1186/2191-219X-1-21
PMCID: PMC3250963  PMID: 22214201
neuropeptide Y receptor; tumor imaging; oncology; peptide receptor radionuclide therapy; breast cancer; antagonist
11.  Switch from Antagonist to Agonist after Addition of a DOTA Chelator to a Somatostatin Analog 
Purpose
Peptide receptor targeting has become an increasingly attractive method to target tumors diagnostically and radiotherapeutically. Peptides linked to a variety of chelators have been developed for this purpose. They have, however rarely been tested for their agonistic or antagonistic properties. We report here on a somatostatin antagonist that switched to an agonist upon coupling to a DOTA chelator.
Methods
Two novel somatostatin analogs, 406-040-15 and its DOTA-coupled counterpart 406-051-20, with and without cold Indium-labeling, were tested for their sst1-sst5 binding affinity using receptor autoradiography. Moreover, they were tested functionally for their ability to affect sst2 and sst3 internalization in vitro in HEK293 cells stably expressing the human sst2 or sst3 receptor, using an immunofluorescence microscopy based internalization assay.
Results
All three compounds were characterized as pan-somatostatin analogs having a high affinity for all five somatostatin receptor subtypes. In the sst2 internalization assay, all three compounds showed an identical behavior, namely a weak agonistic effect complemented by a weak antagonistic effect, compatible with the behavior of a partial agonist. Conversely, in the sst3 internalization assay, 406-040-15 was a full antagonist whereas its DOTA counterpart, 406-051-20, with and without Indium-labeling, switched to a full agonist.
Conclusions
Adding the DOTA chelator to the somatostatin analog 406-040-15 triggers a switch at sst3 receptor from an antagonist to an agonist. This indicates that potential radioligands for tumor targeting should be always tested functionally before further development, in particular if a chelator is added.
doi:10.1007/s00259-010-1445-x
PMCID: PMC3025705  PMID: 20396884
Somatostatin receptors; agonists; antagonists; chelators; receptor internalization; functional assays
12.  Three-dimensional consensus structure of sst2-selective somatostatin (SRIF) antagonists by NMR 
Biopolymers  2008;89(12):1077-1087.
The three-dimensional NMR structures of seven octapeptide analogs of somatostatin (SRIF), based on octreotide, with the basic sequence H-Cpa/Phe2-c[DCys3-Xxx7-DTrp/DAph(Cbm)8-Lys9-Thr10-Cys14]-Yyy-NH2 (the numbering refers to the position in native SRIF), with Xxx7 being Aph(Cbm)/Tyr/Agl(NMe,benzoyl) and Yyy being Nal/DTyr/Thr, are presented here. Most of these analogs exhibit potent and highly selective binding to sst2 receptors and all of the analogs are antagonists inhibiting receptor signaling. Based on their consensus 3D structure, the pharmacophore of the sst2-selective antagonist has been defined. The pharmacophore involves the side chains of Cpa2, DTrp/DAph(Cbm)8 and Lys9 with the backbone, for most of sst2-selective antagonists are comprised of a type-II’ β-turn. Hence, the sst2-selective antagonist pharmacophore is very similar to the sst2-selective agonist pharmacophore previously described.
doi:10.1002/bip.21060
PMCID: PMC2789648  PMID: 18655144
13.  Ring size of somatostatin analogues (ODT-8) modulates receptor selectivity and binding affinity 
Journal of medicinal chemistry  2008;51(9):2668-2675.
The synthesis, biological testing and NMR studies of several analogues of H-c[Cys3-Phe6-Phe7-dTrp8-Lys9-Thr10-Phe11-Cys14]-OH (ODT-8, a pan-somatostatin analogue) (1), have been performed to assess the effect of changing the stereochemistry and the number of the atoms in the disulfide bridge on binding affinity. Cysteine at positions 3 and/or 14 (SRIF numbering) were/was substituted with d-cysteine, Nor-cysteine, d-Nor-cysteine, Homo-cysteine and/or d-Homo-cysteine. The 3D structures of selected partially selective, bioactive analogues (3, 18, 19 and 21) were carried out in DMSO. Interestingly and not unexpectedly, the 3D structures of these analogues comprised the pharmacophore for which the analogues had the highest binding affinities (i.e., sst4 in all cases).
doi:10.1021/jm701444y
PMCID: PMC2782568  PMID: 18410084
14.  Delayed Satiety-Like Actions and Altered Feeding Microstructure by a Selective Type 2 Corticotropin-Releasing Factor Agonist in Rats: Intra-Hypothalamic Urocortin 3 Administration Reduces Food Intake by Prolonging the Post-Meal Interval 
Brain corticotropin-releasing factor/urocortin (CRF/Ucn) systems are hypothesized to control feeding, with central administration of ‘type 2’ urocortins producing delayed anorexia. The present study sought to identify the receptor subtype, brain site, and behavioral mode of action through which Ucn 3 reduces nocturnal food intake in rats. Non-food-deprived male Wistar rats (n = 176) were administered Ucn 3 into the lateral (LV) or fourth ventricle, or into the ventromedial or paraventricular nuclei of the hypothalamus (VMN, PVN) or the medial amygdala (MeA), regions in which Ucn 3 is expressed in proximity to CRF2 receptors. LV Ucn 3 suppressed ingestion during the third–fourth post-injection hours. LV Ucn 3 anorexia was reversed by cotreatment with astressin2-B, a selective CRF2 antagonist and not observed following equimole subcutaneous or fourth ventricle administration. Bilateral intra-VMN and intra-PVN infusion, more potently than LV infusion, reduced the quantity (57–73%) and duration of ingestion (32–68%) during the third–fourth post-infusion hours. LV, intra-PVN and intra-VMN infusion of Ucn 3 slowed the eating rate and reduced intake by prolonging the post-meal interval. Intra-VMN Ucn 3 reduced feeding bout size, and intra-PVN Ucn 3 reduced the regularity of eating from pellet to pellet. Ucn 3 effects were behaviorally specific, because minimal effective anorectic Ucn 3 doses did not alter drinking rate or promote a conditioned taste aversion, and site-specific, because intra-MeA Ucn 3 produced a nibbling pattern of more, but smaller meals without altering total intake. The results implicate the VMN and PVN of the hypothalamus as sites for Ucn 3-CRF2 control of food intake.
doi:10.1038/sj.npp.1301214
PMCID: PMC2748839  PMID: 17019404
urocortin 1 or urocortin 3; corticotropin-releasing factor or corticotropin-releasing hormone; ventromedial hypothalamic nucleus or paraventricular nucleus of the hypothalamus; medial amygdala; meal pattern or microstructure; food intake or feeding
15.  Amyloid as a Depot for the Formulation of Long-Acting Drugs  
PLoS Biology  2008;6(2):e17.
Amyloids are highly organized protein aggregates that are associated with both neurodegenerative diseases such as Alzheimer disease and benign functions like skin pigmentation. Amyloids self-polymerize in a nucleation-dependent manner by recruiting their soluble protein/peptide counterpart and are stable against harsh physical, chemical, and biochemical conditions. These extraordinary properties make amyloids attractive for applications in nanotechnology. Here, we suggest the use of amyloids in the formulation of long-acting drugs. It is our rationale that amyloids have the properties required of a long-acting drug because they are stable depots that guarantee a controlled release of the active peptide drug from the amyloid termini. This concept is tested with a family of short- and long-acting analogs of gonadotropin-releasing hormone (GnRH), and it is shown that amyloids thereof can act as a source for the sustained release of biologically active peptides.
Author Summary
Amyloids are highly organized protein aggregates that are associated with both neurodegenerative diseases such as Alzheimer disease and benign functions such as skin pigmentation. Amyloids self-polymerize by recruiting their soluble protein counterpart and remain stable against harsh physical, chemical, and biochemical conditions. These extraordinary properties make amyloids attractive for applications in nanotechnology. Here, we suggest the use of amyloids in the formulation of long-acting drugs, which are active over extended periods of days and weeks. Long-acting drugs have been designed to increase patient comfort, convenience, dosage accuracy, and assurance of patient compliance for drugs that have a low oral bioavailability. It is our rationale that amyloids have the properties required of a long-acting drug because they are stable depots that guarantee a controlled release of the active peptide drug from the amyloid termini. This concept is tested with a family of short- and long-acting analogs of gonadotropin-releasing hormone, and it is shown that amyloids thereof can act as a source for the sustained release of biologically active peptides.
Amyloids have the properties required of a long-acting drug because they are stable depots that guarantee a controlled release of the active peptide drug from the amyloid termini.
doi:10.1371/journal.pbio.0060017
PMCID: PMC2225439  PMID: 18254658

Results 1-15 (15)