Abstract
Over the last two decades, the potential usage of cell-penetrating peptides (CPPs) for the intracellular delivery of various molecules has prompted the identification of novel peptidic identities. However, cytotoxic effects and unpredicted immunological responses have often limited the use of various CPP sequences in the clinic. To overcome these issues, the usage of endogenous peptides appears as an appropriate alternative approach. The hormone pituitary adenylate-cyclase-activating polypeptide (PACAP38) has been recently identified as a novel and very efficient CPP. This 38-residue polycationic peptide is a member of the secretin/glucagon/growth hormone-releasing hormone (GHRH) superfamily, with which PACAP38 shares high structural and conformational homologies. In this study, we evaluated the cell-penetrating ability of cationic peptide hormones in the context of the expression of cell surface glycosaminoglycans (GAGs). Our results indicated that among all peptides evaluated, PACAP38 was unique for its potent efficiency of cellular uptake. Interestingly, the abilities of the peptides to reach the intracellular space did not correlate with their binding affinities to sulfated GAGs, but rather to their capacity to clustered heparin in vitro. This study demonstrates that the uptake efficiency of a given cationic CPP does not necessarily correlate with its affinity to sulfated GAGs and that its ability to cluster GAGs should be considered for the identification of novel peptidic sequences with potent cellular penetrating properties.
Highlights
Cell-penetrating peptides (CPPs) are polypeptides generally encompassing between five and 30 residues, which can readily cross the cellular plasma membrane through different mechanisms that still remain the matter of active debates [1]
We evaluated the uptake of peptides from the secretin/glucagon/growth hormone-releasing hormone (GHRH) and of calcitonin, a peptide hormone for which several fragments are known to translocate cellular membranes [15]
It has been previously shown that the hormone PACAP38 and several of its derivatives are efficiently competent to cross the plasma membrane and to deliver a variety of cargoes inside the cell [5,6]
Summary
Cell-penetrating peptides (CPPs) are polypeptides generally encompassing between five and 30 residues, which can readily cross the cellular plasma membrane through different mechanisms that still remain the matter of active debates [1]. As recently reported for PACAP38 [13], the cellular uptake of representative peptides of the plasma mesmecrbertiann/gelu[c1a8g]o.nI/nGHcoRnHtrpaespt,tiednedsoucpyertfoasmisilyofwcaaslcpitaortniailnlyadpeppeeandrsentto obne itnhedeppreesnendceenotfotfhceell surface GAGs, as ptholeyseaxcctheanritdoe-fdoinmtaeirnns oaflipzraotteioognlywcanass, arsactehlleurlarsiumptialkaers winerKe 310%antod50p%gslo-wAe-r7f4or5GCAHGsO-decfeiclilesn.t This is in agreementCwHiOth-ptghs-eAm-74a5incemllseccohmapnarisedmtso othfeiinr tweirldn-atylipzeactoiounnteprrpoarptoCsHeOd-fKo1rccealllsc(iFtiognurine 1aBn).dCiHtsO9p–g3s2- fragment conferringAa-7k4e5ycerlloslaereodfenficeigenattiinvxeylyloscyhltararngsefedrapseh,oanspenhzoylmipeitdhasticnatapleyzpetsidthee tcreanllsufelraorfuapD-txaykloesy[1l g5r]o.uIpn addition, to the side chain of a serine, a key step in the synthesis of proteoglycans As a consequence, these cells calcitonin ddoisnpotlaeyxpsreosns laynyoGnAeGpsoosnittihveeoluytecrhleaarfgleetdof rtheesiirdpulaes,maa Lmyesmabrtapneo[s1i8t]i.oInn c1o8nt(rTasatb, elned1o)c,ytsousigs gestive of poor putatoifvcealecilteocntinroasptpaetaircs itontbeeriandcteipoenndsewntiothf ceslul slufarftaecde GGAAGGs, sa.s the extent of internalization was rather similar in K1 and pgs-A-745 CHO cells. Data are expressed as a function of (A) heparin/peptide molar ratio or (B) peptide/heparin molar ratio. 6
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