Urotensin core mimics that modulate the biological activity of urotensin-II related peptide but not urotensin-II

Strack, Martin; Billard, Étienne; Chatenet, David; Lubell, William D.

doi:10.1016/j.bmcl.2017.05.088

Cited by 11 publications

(19 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this study, 1,4‐ and 1,5‐disubstituted 1,2,3‐triazole of UII (4–11) possess distinct binding parameters and biological profile . While these analogs were constructed around the UII (4–11) sequence, the conception of two 1,4‐disubstituted 1,2,3‐triazole mimicking the bioactive core sequence of both UII and URP c(Gly‐Trp‐Lys‐Tyr‐Glyψ(tz)) (Figure ) and c(Gly‐Phe‐Trp‐Lys‐Tyr‐Glyψ(tz)) (Figure ) has produced two UT allosteric modulators . Notably, c(Gly‐Phe‐Trp‐Lys‐Tyr‐Glyψ(tz)) was able to decrease URP‐mediated contraction (around 50% of the total URP‐mediated contraction) while leaving completely unaffected UII‐mediated contraction.…”

Section: Disulfide Modification: a Bridge To Allosteric Modulatorsmentioning

confidence: 98%

“…So far, none of the UT antagonists has been investigated for their ability to also block URP‐mediated function. However, recently developed peptidic and non‐peptidic UT antagonists have demonstrated a wide range of activity against UII‐ and URP‐mediated function . For instance, R‐4a (Figure ) inhibited completely hUII‐induced contractions but increased tremendously URP‐associated vasoconstriction .…”

Section: Nonpeptidic Antagonists With Probe‐dependent Functionsmentioning

confidence: 99%

See 1 more Smart Citation

New directions for urotensin II receptor ligands

et al. 2018

Self Cite

View full text Add to dashboard Cite

The urotensinergic system, formed by a G protein‐coupled receptor (GPCR) termed UT and two endogenous peptide ligands Urotensin II (UII, H‐Glu‐Thr‐Pro‐Asp‐[Cys‐Phe‐Trp‐Lys‐Tyr‐Cys]‐Val‐OH) and Urotensin II‐related peptide (URP, H‐Ala‐[Cys‐Phe‐Trp‐Lys‐Tyr‐Cys]‐Val‐OH), is currently regarded as a potential key contributor to cardiovascular functions. While multiple animal studies have shown the therapeutic potential of UT ligands for the treatment of heart failure and atherosclerosis, their lack of efficacy in clinical studies points toward a greater understanding of UT pharmacology at both the molecular and cellular levels. UII and URP are cyclic peptides that share a common and strictly conserved bioactive cyclic core (‐Cys‐Phe‐Trp‐Lys‐Tyr‐Cys‐) but differ by their extracyclic N‐terminal residues. While sharing common biological activity, these two endogenous ligands appear to be functionally selective, displaying different specific effects through the selection/stabilization of particular UT active conformations. Thus, UII and URP should be regarded as two distinct actors in the control of cardiovascular functions. In this regard, more focus on URP biological effects had to be paid, while systematic evaluation of new antagonists against both endogenous ligands appears mandatory. Overall, this review offers an overview of the actual horizon of UT pharmacology, notably concerning the development of biased ligands and allosteric modulators.

show abstract

Section: Disulfide Modification: a Bridge To Allosteric Modulatorsmentioning

confidence: 98%

Section: Nonpeptidic Antagonists With Probe‐dependent Functionsmentioning

confidence: 99%

New directions for urotensin II receptor ligands

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…264 When a short spacer on the C-terminus is desired for headto-tail cyclization, it is possible to introduce a C-terminal propargylamine by using a silyl-based alkyne modifying (SAM)-resin. 272,273 CuAAC does not require protecting groups and can be performed on-resin 267,271,[274][275][276][277][278] as well as in solution, 262,[265][266][267][268][269][279][280][281][282][283][284][285][286][287][288][289][290][291][292][293][294][295] which is more common and proceeds under mild conditions. Cu salts most frequently used are CuSO 4 with sodium ascorbate, or Cu I salts such as CuI and…”

Section: C-c Triple Bond Formation: Ringclosing Alkyne Metathesismentioning

confidence: 99%

“… 264 When a short spacer on the C-terminus is desired for head-to-tail cyclization, it is possible to introduce a C-terminal propargylamine by using a silyl-based alkyne modifying (SAM)-resin. 272,273 …”

Section: Triazole Formationmentioning

confidence: 99%

Macrocyclization strategies for cyclic peptides and peptidomimetics

2021

View full text Add to dashboard Cite

show abstract

“…Contingent on their interactions with UT, UII and URP probably induce distinct UT conformational and dynamic changes that lead to divergent signaling profiles with both common and distinct biological activities (2,(17)(18)(19)(20)(21). Recent years have witnessed the emergence of useful molecules, with probe-dependent actions, that could shed light on the respective roles and importance of UII and URP under normal and pathological conditions (13,17,18,(22)(23)(24)(25)(26)(27).…”

Section: Introductionmentioning

confidence: 99%

Membrane-tethered peptides derived from intracellular loops 2 and 3 of the urotensin II receptor act as allosteric biased ligands

Nassour

Hoang

Martin

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Over the last decade, the urotensinergic system has garnered significant attention as a promising new target for the treatment of various cardiovascular diseases and also cancer. Significant investment toward the development of clinically relevant UT ligands for therapeutic intervention has been made but have met little to no success to date. The UT system, which has yet to be effectively targeted, therefore remains to be therapeutically exploited. The discovery of allosteric sites that allow modulation of receptor activity will increase the searchable chemical space against a disease-relevant target. Pepducins and other lipidated peptides have been used as both mechanistic probes and potential therapeutics. Therefore, pepducins derived from the human urotensin II receptor might represent unique tools to generate signaling bias and study UT signaling networks. Two hUT-derived pepducins, derived from the second and the third intracellular loop of UT, respectively, have been synthesized and pharmacologically characterized. Our results demonstrated that hUT-Pep2 and [Trp1, Leu2]hUT-Pep3 acted as biased ago-allosteric modulators, triggered ERK1/2 phosphorylation and to a lesser extent, IP1 production, stimulated cell proliferation yet were devoid of contractile activity. Interestingly, both hUT-derived pepducins were able to modulate hUII- and URP-mediated contraction albeit to different extents. These new derivatives represent unique tools to reveal the intricacies of hUT signaling and also a novel avenue to design allosteric ligands selectively targeting UT signaling that could prove to be useful for the treatment of hUT-associated diseases.

show abstract

Urotensin core mimics that modulate the biological activity of urotensin-II related peptide but not urotensin-II

Cited by 11 publications

References 42 publications

New directions for urotensin II receptor ligands

New directions for urotensin II receptor ligands

Macrocyclization strategies for cyclic peptides and peptidomimetics

Membrane-tethered peptides derived from intracellular loops 2 and 3 of the urotensin II receptor act as allosteric biased ligands

Contact Info

Product

Resources

About