2021
DOI: 10.1021/acs.jmedchem.0c01533
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Identification of Potent and Long-Acting Single-Chain Peptide Mimetics of Human Relaxin-2 for Cardiovascular Diseases

Abstract: The insulin-like peptide human relaxin-2 was identified as a hormone that, among other biological functions, mediates the hemodynamic changes occurring during pregnancy. Recombinant relaxin-2 (serelaxin) has shown beneficial effects in acute heart failure, but its full therapeutic potential has been hampered by its short halflife and the need for intravenous administration limiting its use to intensive care units. In this study, we report the development of long-acting potent single-chain relaxin peptide mimet… Show more

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Cited by 24 publications
(33 citation statements)
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“…This unique mode of interaction of RLX with its receptor has represented a challenge for the generation of effective RXFP1 agonists. To date, three different conceptual pathways have been explored, namely: peptide and non-peptide RXFP1 agonists designed on receptor complementarity ( Shemesh et al, 2009 ; Xiao et al, 2013 ; Agoulnik et al, 2017 ), low molecular weight RLX analogues designed on the functional B chain domains ( Hossain et al, 2016 ; Marshall et al, 2017 ; Mallart et al, 2021 ) and semi-synthetic double-chain RLX analogues modified to extend their half-life ( Muppidi et al, 2019 ). Another approach focuses on H1 RLX, whose gene Rln1 is only present in primates as a likely ortholog of the RLX-encoding gene Rln2 ( Hansell et al, 1991 ).…”
Section: Introductionmentioning
confidence: 99%
“…This unique mode of interaction of RLX with its receptor has represented a challenge for the generation of effective RXFP1 agonists. To date, three different conceptual pathways have been explored, namely: peptide and non-peptide RXFP1 agonists designed on receptor complementarity ( Shemesh et al, 2009 ; Xiao et al, 2013 ; Agoulnik et al, 2017 ), low molecular weight RLX analogues designed on the functional B chain domains ( Hossain et al, 2016 ; Marshall et al, 2017 ; Mallart et al, 2021 ) and semi-synthetic double-chain RLX analogues modified to extend their half-life ( Muppidi et al, 2019 ). Another approach focuses on H1 RLX, whose gene Rln1 is only present in primates as a likely ortholog of the RLX-encoding gene Rln2 ( Hansell et al, 1991 ).…”
Section: Introductionmentioning
confidence: 99%
“…Although the presence of the positively charged Lys patch may be suspected to induce some side effects, it was successfully used in active peptide sequences including the recently disclosed RXFP1 agonist peptides and for the development of the potent GLP-1 receptor agonist, Lixisenatide. [45][46][47][48] In this study, we hypothesized that besides the reported properties of the Lys patch, its introduction at the C-terminus of Pep2-8 derivatives would lead to additional electrostatic interactions with proximal negative side chains at the PCSK9 surface (Figure 1C).…”
Section: Introductionmentioning
confidence: 99%
“…Versions of relaxin’s B-chain have been produced and tested for activity at RXFP1, however, the B-chain alone shows low signaling potency, with an EC 50 of around 7 μM (20). Optimization of B-chain only variants and the addition of lipid modifications resulted in peptides able to activate RXFP1 with improved potency and half-lives of up to 9 hours (21). Additionally, studies with mouse models of heart failure have recently tested a fusion between relaxin-2 and an antibody Fc, however no details of the protein sequence or engineering methods were reported (22).…”
Section: Introductionmentioning
confidence: 99%