A spectroscopic and molecular dynamics study on the aggregation process of a long-acting lipidated therapeutic peptide: the case of semaglutide

Venanzi, Mariano; Savioli, Marco; Cimino, Rita; Gatto, Emanuela; Palleschi, Antonio; Ripani, Giorgio; Cicero, Daniel O.; Placidi, E.; Orvieto, Federica; Bianchi, Elisabetta

doi:10.1039/d0sm01011a

Cited by 15 publications

(17 citation statements)

References 38 publications

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“…In this regard, it is important to stress that formation of peptide fibrils necessitates of specific peptide-peptide interaction. 37,38 MD simulations suggest that an inter-strand HB network concurs to stabilize peptide clusters, and these interactions could be the basis of the clear directionality observed in the formation of fibrillar aggregates from the coalescence of globular structures.…”

Section: Discussionmentioning

confidence: 98%

Formulation matters! A spectroscopic and molecular dynamics investigation on the peptide CIGB552 as itself and in its therapeutical formulation

Savioli

Antonelli

Bocchinfuso

et al. 2021

Journal of Peptide Science

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Synthetic therapeutic peptides (STP) are intensively studied as new‐generation drugs, characterized by high purity, biocompatibility, selectivity and stereochemical control. However, most of the studies are focussed on the bioactivity of STP without considering how the formulation actually used for therapy administration could alter the physico‐chemical properties of the active principle. The aggregation properties of a 20‐mer STP (Ac‐His‐Ala‐Arg‐Ile‐Lys‐D‐Pro‐Thr‐Phe‐Arg‐Arg‐D‐Leu‐Lys‐Trp‐Lys‐Tyr‐Lys‐Gly‐Lys‐Phe‐Trp‐NH2), showing antitumor activity, were investigated by optical spectroscopy and atomic force microscopy imaging, as itself (CIGB552) and in its therapeutic formulation (CIGB552TF). It has found that the therapeutic formulation deeply affects the aggregation properties of the investigated peptide and the morphology of the aggregates formed on mica by deposition of CIGB552 and CIGB552TF millimolar solutions. Molecular dynamics simulations studied the first steps of CIGB552 aggregation under physiological ionic strength conditions (NaCl 150 mM), showing that peptide oligomers, from dimers to tetramers, are preferentially formed in this environment. Interestingly, cell viability assays performed on H‐460 cell lines indicate a major antiproliferative activity of the peptide in its therapeutic formulation with respect to the peptide aqueous solution.

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Section: Discussionmentioning

confidence: 98%

Formulation matters! A spectroscopic and molecular dynamics investigation on the peptide CIGB552 as itself and in its therapeutical formulation

Savioli

Antonelli

Bocchinfuso

et al. 2021

Journal of Peptide Science

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“…The strategy behind the case studies discussed in this contribution is based on the restriction of the conformational landscape of the peptide building blocks with the aim to reduce the entropy penalty associated with the formation of aggregates in solution or thin films at the air/liquid interface. Lipidation is an alternative way to control the structuration of peptide aggregates, affecting the pharmacokinetics and bioavailability of therapeutic peptides [ 103 ]. The still-open question is if peptide nanostructures may affect per se the target/drug recognition process or if they simply impinge upon the secretion processes determining the drug retention.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, we investigated the aggregation properties of semaglutide (SMG), a therapeutic 37-mer peptide against type-II diabetes [ 103 ]. In the SMG analogue investigated, the Ala residue at position 8 was replaced with an Aib, and the Lys at position 26 was derivatized in the side chain by two consecutive PEG groups, a γ-Glu residue.…”

Section: Self-assembled Peptide Nanostructures: From Models To Therapymentioning

confidence: 99%

“…The insertion of an Aib residue at the N-terminus would contribute to inhibit enzymatic degradation. Early on, SMG showed good solubility in aqueous solutions, as only monomers and small oligomers (mainly dimers) could be devised from the small hydrodynamic volumes and the fast correlation times predicted by fluorescence anisotropy measurements and MD simulations, respectively [ 103 ]. In contrast, at long lengths of time (weeks), experimental evidence strongly suggested that a steady aggregation process was taking place.…”

Section: Self-assembled Peptide Nanostructures: From Models To Therapymentioning

confidence: 99%

“…Lys(26) side chains are shown in green. Adapted with permission from [ 103 ] (Copyright Royal Society of Chemistry 2020).…”

Section: Figures and Schemementioning

confidence: 99%

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Peptide Self-Assembled Nanostructures: From Models to Therapeutic Peptides

2022

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Self-assembly is the most suitable approach to obtaining peptide-based materials on the nano- and mesoscopic scales. Applications span from peptide drugs for personalized therapy to light harvesting and electron conductive media for solar energy production and bioelectronics, respectively. In this study, we will discuss the self-assembly of selected model and bioactive peptides, in particular reviewing our recent work on the formation of peptide architectures of nano- and mesoscopic size in solution and on solid substrates. The hierarchical and cooperative characters of peptide self-assembly will be highlighted, focusing on the structural and dynamical properties of the peptide building blocks and on the nature of the intermolecular interactions driving the aggregation phenomena in a given environment. These results will pave the way for the understanding of the still-debated mechanism of action of an antimicrobial peptide (trichogin GA IV) and the pharmacokinetic properties of a peptide drug (semaglutide) currently in use for the therapy of type-II diabetes.

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Design and Development of a New Glucagon-Like Peptide-1 Receptor Agonist to Obtain High Oral Bioavailability

Chen

Shi

et al. 2022

Pharm Res

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A spectroscopic and molecular dynamics study on the aggregation process of a long-acting lipidated therapeutic peptide: the case of semaglutide

Abstract: The aggregation properties of Semaglutide, a lipidated peptide drug agonist of the Glucagon-like peptide 1 receptor recently approved for treatment of diabetes type 2, have been investigated by spectroscopic techniques...

Cited by 15 publications

References 38 publications

Formulation matters! A spectroscopic and molecular dynamics investigation on the peptide CIGB552 as itself and in its therapeutical formulation

Formulation matters! A spectroscopic and molecular dynamics investigation on the peptide CIGB552 as itself and in its therapeutical formulation

Peptide Self-Assembled Nanostructures: From Models to Therapeutic Peptides

Design and Development of a New Glucagon-Like Peptide-1 Receptor Agonist to Obtain High Oral Bioavailability

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