- Investigating the phosphinic acid tripeptide mimetic DG013A as a tool compound inhibitor of the M1-aminopeptidase ERAP1
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ERAP1 is a zinc-dependent M1-aminopeptidase that trims lipophilic amino acids from the N-terminus of peptides. Owing to its importance in the processing of antigens and regulation of the adaptive immune response, dysregulation of the highly polymorphic ERAP1 has been implicated in autoimmune disease and cancer. To test this hypothesis and establish the role of ERAP1 in these disease areas, high affinity, cell permeable and selective chemical probes are essential. DG013A 1, is a phosphinic acid tripeptide mimetic inhibitor with reported low nanomolar affinity for ERAP1. However, this chemotype is a privileged structure for binding to various metal-dependent peptidases and contains a highly charged phosphinic acid moiety, so it was unclear whether it would display the high selectivity and passive permeability required for a chemical probe. Therefore, we designed a new stereoselective route to synthesize a library of DG013A 1 analogues to determine the suitability of this compound as a cellular chemical probe to validate ERAP1 as a drug discovery target.
- Wilding, Birgit,Pasqua, A. Elisa,E. A. Chessum, Nicola,Pierrat, Olivier A.,Hahner, Tamas,Tomlin, Kathy,Shehu, Erald,Burke, Rosemary,Richards, G. Meirion,Whitton, Bradleigh,Arwert, Esther N.,Thapaliya, Arjun,Salimraj, Ramya,van Montfort, Rob,Skawinska, Agi,Hayes, Angela,Raynaud, Florence,Chopra, Rajesh,Jones, Keith,Newton, Gary,Cheeseman, Matthew D.
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supporting information
(2021/05/06)
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- Phosphinotripeptidic inhibitors of leucylaminopeptidases
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Phosphinate pseudopeptide are analogs of peptides containing phosphinate moiety in a place of the amide bond. Due to this, the organophosphorus fragment resembles the tetrahedral transition state of the amide bond hydrolysis. Additionally, it is also capable of coordinating metal ions, for example, zinc or magnesium ions. These two properties of phosphinate pseudopeptides make them an ideal candidate for metal-related protease inhibitors. This research investigates the influence of additional residue in the P2 position on the inhibitory properties of phosphinopeptides. The synthetic strategy is proposed, based on retrosynthetic analysis. The N-C-P bond formation in the desired compounds is conveniently available from the three-component condensation of appropriate amino components, aldehydes, and hypophosphorous acid. One of the crucial synthetic steps is the careful selection of the protecting groups for all the functionals. Determination of the inhibitor activity of the obtained compounds has been done using UV-Vis spectroscopy and standard substrate L-Leu-p-nitroanilide toward the enzymes isolated from the porcine kidney (SsLAP, Sus scrofa Leucine aminopeptidase) and barley seeds (HvLAP, Hordeum vulgare Leucine aminopeptidase). An efficient procedure for the preparation of phosphinotripeptides has been performed. Activity test shown that introduction of additional residue into P2 position obtains the micromolar range inhibitors of SsLAP and HvLAP. Moreover, careful selection of the residue in the P2 position should improve its selectivity toward mammalian and plant leucyl aminopeptidases.
- Jewgiński, Micha?,Haremza, Kinga,de los Santos, Jesús M.,Sbai, Zouhair Es,Oszywa, Bartosz,Pawe?czak, Ma?gorzata,Palacios, Francisco,Latajka, Rafa?
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- Facile synthesis of bis-α-aminoalkylphosphinates
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Herein we report a facile synthesis of esters of bis-α- aminoalkylphosphinic acids obtained by an addition of Cbz-protected phosphinic analogues of amino acid methyl esters to an appropriate imine in refluxing benzene. Complete deprotection of the esters
- Drag, Marcin,Dlugosz, Katarzyna,Oleksyszyn, Jozef
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p. 2787 - 2795
(2007/10/03)
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