Highly Potent Nociceptin Analog Containing the Arg-Lys Triple Repeat

Okada, Kazushi; Sujaku, Tetsujo; Chuman, Yoshiro; Nakashima, Rie; Nose, Takeru; Costa, Tommaso; Yamada, Yoshinari; Yokoyama, Masayuki; Nagahisa, Atsushi; Shimohigashi, Yasuyuki

doi:10.1006/bbrc.2000.3822

Cited by 74 publications

(70 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…3B, 4B, 5B, and 6B), but under the same conditions all of the constrained peptides (20,22,24,26) showed α-helicity (45-92%, Figs. 3B, 4B, 5B, and 6B).…”

Section: Discussionmentioning

confidence: 87%

“…3-6). Our objective was to compare short peptide sequences corresponding to different protein α-helices (or putative α-helices) in both unconstrained (19,21,23,25) and α-helix-constrained (20,22,24,26) forms. By comparatively assessing the extent of induction of α-helical structure, serum stability, and biological activity, we could determine if this approach had general utility to mimicking protein α-helices in small molecules.…”

Section: Resultsmentioning

confidence: 99%

“…We also chose to mimic a "superagonist" of the G protein-coupled receptor known as ORL-1 based on the native ligand nociceptin(1-17), a peptide hormone important in sensory perception and pain. This unstructured peptide has a putative α-helical address domain (ARKSARKLANQ) and an unstructured N-terminal message domain (FGGF), both of which may become structured as a helix and turn respectively, upon binding in or near the membrane (25,26). In water native nociceptin(1-17) has negligible helicity (<6%), as has a more potent agonist analogue containing a parafluoro-phenylalanine at position 4 and lysine at position 15 (25, Fig.…”

Section: Resultsmentioning

confidence: 99%

“…3B, 4B, 5B, and 6B). Helicity was induced by either two back-to-back cyclic pentapeptides (20,22) or two adjacent cyclic pentapeptides separated by two amino acids (24,26). Helix preorganization resulted in significant enhancements (9-, 10-, 1,000-, and 10,000-fold) in affinity/activity over unconstrained analogues, these functional responses being similar or greater than for the native proteins from which they were derived.…”

Section: Discussionmentioning

confidence: 99%

“…Final structures had no distance (>0.2 Å) or angle (>5°) violations and were deposited with all NMR data in Biological Magnetic Resonance Bank. Accession numbers: 3z0q0z1 (compound 1), 3z0q0z2 (20), 3z0q0z3 (22), 3z0q0z4 (24), and 3z0q0z0 (26).…”

Section: Methodsmentioning

confidence: 99%

See 4 more Smart Citations

Downsizing human, bacterial, and viral proteins to short water-stable alpha helices that maintain biological potency

Harrison

Shepherd²,

Hoang³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

171

166

View full text Add to dashboard Cite

Recombinant proteins are important therapeutics due to potent, highly specific, and nontoxic actions in vivo. However, they are expensive medicines to manufacture, chemically unstable, and difficult to administer with low patient uptake and compliance. Small molecule drugs are cheaper and more bioavailable, but less target-specific in vivo and often have associated side effects. Here we combine some advantages of proteins and small molecules by taking short amino acid sequences that confer potency and selectivity to proteins, and fixing them as small constrained molecules that are chemically and structurally stable and easy to make. Proteins often use short α-helices of just 1-4 helical turns (4-15 amino acids) to interact with biological targets, but peptides this short usually have negligible α-helicity in water. Here we show that short peptides, corresponding to helical epitopes from viral, bacterial, or human proteins, can be strategically fixed in highly α-helical structures in water. These helix-constrained compounds have similar biological potencies as proteins that bear the same helical sequences. Examples are (i) a picomolar inhibitor of Respiratory Syncytial Virus F protein mediated fusion with host cells, (ii) a nanomolar inhibitor of RNA binding to the transporter protein HIV-Rev, (iii) a submicromolar inhibitor of Streptococcus pneumoniae growth induced by quorum sensing pheromone Competence Stimulating Peptide, and (iv) a picomolar agonist of the GPCR pain receptor opioid receptor like receptor ORL-1. This approach can be generally applicable to downsizing helical regions of proteins with broad applications to biology and medicine.helix | inhibitor | structure | mimetic | anti-infective P roteins are key functional components that define life, aging, disease, and death. Their uses in medicine, science, and industry are however limited by their complexity, high costs, chemical instability, and low bioavailability. Consequently, new chemical technology is needed to create simpler, smaller, cheaper, more stable, and bioavailable molecules that can execute or inhibit selected functions of proteins. If generic approaches could be developed to stabilize or recreate new molecular shapes that mimic structural components of proteins (e.g., helices, turns, strands, and combinations), the resulting molecules could potentially be extremely valuable for interrogating biological systems and for exploring prospective applications such as new pharmaceuticals, diagnostics, vaccines, and nanomaterials.Some proteins elicit biological function through a single short α-helical segment (usually 4-15 amino acids in 1-4 helical turns) that interacts with nucleic acids or proteins (1-3). However, short synthetic peptides of this length are usually not thermodynamically stable helices in water and adopt only random structures (4). Techniques developed as generalized strategies for stabilising or mimicking short peptide α-helices have been limited by lack of helical structure in water, by sequence or context dependent helici...

show abstract

“…3B, 4B, 5B, and 6B), but under the same conditions all of the constrained peptides (20,22,24,26) showed α-helicity (45-92%, Figs. 3B, 4B, 5B, and 6B).…”

Section: Discussionmentioning

confidence: 87%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

Downsizing human, bacterial, and viral proteins to short water-stable alpha helices that maintain biological potency

Harrison

Shepherd²,

Hoang³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

171

166

View full text Add to dashboard Cite

show abstract

Potential of Nociceptin/Orphanin FQ Peptide Analogs for Drug Development

Wtorek

Janecka

2020

Chemistry & Biodiversity

View full text Add to dashboard Cite

Nociceptin receptor (NOP) belongs to the family of opioid receptors but was discovered and characterized much later than the so called classical opioid receptors, μ, δ and к (or MOP, DOP and KOP, resp.). Nociceptin/ orphanin FQ (N/OFQ) is the endogenous ligand of this receptor and it controls numerous important functions in the central nervous system and in the periphery, so its analogs may be developed as innovative drugs for the treatment of a variety of conditions and pathological states. Availability of potent and selective ligands with high affinity to NOP receptor is essential to fully understand the role of NOP-N/OFQ system in the body, which in turn may lead to designing novel therapeutics. Here, we have focused on reviewing the structure of potent peptidebased agonists, antagonists, biased analogs and bivalent ligands that target NOP receptor.

show abstract

The Interaction of Highly Helical Structural Mutants with the NOP Receptor Discloses the Role of the Address Domain of Nociceptin/Orphanin FQ

Tancredi

Carrà

Guerrini

et al. 2005

Chemistry A European J

View full text Add to dashboard Cite

Nociceptin is a heptadecapeptide whose sequence is similar to that of Dynorphin A, sharing a message domain characterized by two glycines and two aromatic residues, and a highly basic C-terminal address domain but, in spite of these similarities, displays no opioid activity. Establishing the relative importance of the message and address domains of nociceptin has so far been hampered by its extreme conformational flexibility. Here we show that mutants of this peptide, designed to increase the helical content in the address domain, can be employed to explain the mode of interaction with the NOP receptor. Nociceptin analogues in which Ala residues are substituted with aminoisobutyric acid (Aib) show a substantial increment of activity in their interaction with the NOP receptor. The increment of biological activity was attributed to the well-documented ability of Aib to induce helicity. Here we have verified this working hypothesis by a conformational investigation extended to new analogues in which the role of Aib is taken up by Leu. The NMR conformational analysis confirms that all Ala/Aib peptides as well as [Leu(7,11)]-N/OFQ-amide and [Leu(11,15)]-N/OFQ-amide mutants (N/OFQ=nociceptin/orphanin FQ) have comparable helix content in helix-promoting media. We show that the helical address domain of nociceptin can place key basic residues at an optimal distance from complementary acidic groups of the EL(2) loop of the receptor. Our structural data are used to rationalize pharmacological data which show that although [Leu(11,15)]-N/OFQ-amide has an activity comparable to those of Ala/Aib peptides, [Leu(7,11)]-N/OFQ-amide is less active than N/OFQ-amide. We hypothesize that bulky residues cannot be hosted in or near the hinge region (Thr(5)-Gly(6)-Ala(7)) without severe steric clash with the receptor. This hypothesis is also consistent with previous data on this hinge region obtained by systematic substitution of Thr, Gly, and Ala with Pro.

show abstract

Highly Potent Nociceptin Analog Containing the Arg-Lys Triple Repeat

Cited by 74 publications

References 40 publications

Downsizing human, bacterial, and viral proteins to short water-stable alpha helices that maintain biological potency

Downsizing human, bacterial, and viral proteins to short water-stable alpha helices that maintain biological potency

Potential of Nociceptin/Orphanin FQ Peptide Analogs for Drug Development

The Interaction of Highly Helical Structural Mutants with the NOP Receptor Discloses the Role of the Address Domain of Nociceptin/Orphanin FQ

Contact Info

Product

Resources

About