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1.
J Am Chem Soc ; 144(34): 15519-15528, 2022 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-35972994

RESUMO

Although interest in stabilized α-helical peptides as next-generation therapeutics for modulating biomolecular interfaces is increasing, peptides have limited functionality and stability due to their small size. In comparison, α-helical ligands based on proteins can make steric clash with targets due to their large size. Here, we report the design of a monomeric pseudo-isolated α-helix (mPIH) system in which proteins behave as if they are peptides. The designed proteins contain α-helix ligands that do not require any covalent chemical modification, do not have frayed ends, and importantly can make sterically favorable interactions similar to isolated peptides. An optimal mPIH showed a more than 100-fold increase in target selectivity, which might be related to the advantages in conformational selection due to the absence of frayed ends. The α-helical ligand in the mPIH displayed high thermal stability well above human body temperature and showed reversible and rapid folding/unfolding transitions. Thus, mPIH can become a promising protein-based platform for developing stabilized α-helix pharmaceuticals.


Assuntos
Peptídeos , Proteínas , Sequência de Aminoácidos , Dicroísmo Circular , Humanos , Peptídeos/química , Conformação Proteica em alfa-Hélice , Dobramento de Proteína , Estrutura Secundária de Proteína
2.
Bioorg Med Chem Lett ; 25(22): 5335-8, 2015 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-26421991

RESUMO

A new method for the pre-activation cyclization of a long peptide is described. The approach involves the formation of a pre-activated succinimidyl ester species in advance of amidation, which completely eliminates the potentially troublesome amine end-capping side reaction. The cyclization reactions proceed with high efficiency and fast reaction kinetics for the long peptide with 25 residues. The exploration and large-scale preparation of synthetic cyclic peptides should become more accessible and feasible with this approach. This method has a potential to be further applied for the synthesis of much longer and more complex cyclic peptides.


Assuntos
Aminas/química , Peptídeos Cíclicos/química , Peptídeos/química , Técnicas de Química Analítica , Ciclização , Fatores de Tempo
3.
J Control Release ; 366: 104-113, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38128883

RESUMO

Although peptides notoriously have poor intrinsic pharmacokinetic properties, it is well-known that nanostructures with excellent pharmacokinetic properties can be designed. Noticing that peptide inhibitors are generally nonpolar, here, we consolidate the peptide inhibitor targeting intracellular protein-protein interactions (PPIs) as an integral part of biodegradable self-assembled depsipeptide nanostructures (SdPNs). Because the peptide inhibitor has the dual role of PPI inhibition and self-assembly in this design, problems associated with the poor pharmacokinetics of peptides and encapsulation/entrapment processes can be overcome. Optimized SdPNs displayed better tumor targeting and PPI inhibition properties than the comparable small molecule inhibitor in vivo. Kinetics of PPI inhibition for SdPNs were gradual and controllable in contrast to the rapid inhibition kinetics of the small molecule. Because SdPN is modular, any appropriate peptide inhibitor can be incorporated into the platform without concern for the poor pharmacokinetic properties of the peptide.


Assuntos
Depsipeptídeos , Nanoestruturas , Cinética
4.
ACS Macro Lett ; 5(12): 1406-1410, 2016 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-35651205

RESUMO

The target affinity and selectivity of many biomacromolecules depend on the three-dimensional (3D) distribution of multiple ligands on their surfaces. Here, we devised a self-assembly strategy to control the target-tailored 3D distribution of multiple α-helical ligands on a coiled-coil core scaffold using novel lariat-type supramolecular building blocks. Depending on the coiled-coil composition and ligand grafting sites in the lariat building blocks, the structural and functional features of the self-assembled peptide nanostructures (SPNs) could be variably fine-tuned. Using oligovalent protein-RNA (Rev-RRE) interactions as a model system, we demonstrate that longer grafting reinforces the helicity of the peptide ligands, whereas shorter grafting strengthens the target binding affinity of the SPNs in both monovalent and oligovalent interactions. This supramolecular approach should be useful in developing precisely controllable multivalent ligands for biomacromolecular interactions.

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