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1.
Angew Chem Int Ed Engl ; 63(38): e202407037, 2024 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-38767062

RESUMO

The stimulator of interferon genes (STING) pathway is a potent therapeutic target for innate immunity. Despite the efforts to develop pocket-dependent small-molecule STING agonists that mimic the endogenous STING ligand, cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), most of these agonists showed disappointing results in clinical trials owing to the limitations of the STING pocket. In this study, we developed novel pocket-independent STING-activating agonists (piSTINGs), which act through multivalency-driven oligomerization to activate STING. Additionally, a piSTING-adjuvanted vaccine elicited a significant antibody response and inhibited tumour growth in therapeutic models. Moreover, a piSTING-based vaccine combination with aPD-1 showed remarkable potential to enhance the effectiveness of immune checkpoint blockade (ICB) immunotherapy. In particular, piSTING can strengthen the impact of STING pathway in immunotherapy and accelerate the clinical translation of STING agonists.


Assuntos
Proteínas de Membrana , Proteínas de Membrana/agonistas , Proteínas de Membrana/metabolismo , Humanos , Animais , Camundongos , Imunoterapia , Nucleotídeos Cíclicos/química , Nucleotídeos Cíclicos/farmacologia
2.
Angew Chem Int Ed Engl ; 63(31): e202402880, 2024 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-38758629

RESUMO

Lysine-specific peptide and protein modification strategies are widely used to study charge-related functions and applications. However, these strategies often result in the loss of the positive charge on lysine, significantly impacting the charge-related properties of proteins. Herein, we report a strategy to preserve the positive charge and selectively convert amines in lysine side chains to amidines using nitriles and hydroxylamine under aqueous conditions. Various unprotected peptides and proteins were successfully modified with a high conversion rate. Moreover, the reactive amidine moiety and derived modification site enable subsequent secondary modifications. Notably, positive charges were retained during the modification. Therefore, positive charge-related protein properties, such as liquid-liquid phase separation behaviour of α-synuclein, were not affected. This strategy was subsequently applied to a lysine rich protein to develop an amidine-containing coacervate DNA complex with outstanding mechanical properties. Overall, our innovative strategy provides a new avenue to explore the characteristics of positively charged proteins.


Assuntos
Hidroxilamina , Lisina , Lisina/química , Hidroxilamina/química , Proteínas/química , Amidinas/química , alfa-Sinucleína/química , Peptídeos/química
3.
J Pept Sci ; 29(3): e3454, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36181422

RESUMO

Considering the fact that site-selective late-stage diversification of peptides and proteins remains a challenge for biochemistry, strategies targeting low-abundance natural amino acids need to be further developed. As an extremely oxidation-sensitive and low-abundance amino acid, methionine emerges as a promising target for chemo- and site-selective modification. Herein we report an efficient and highly selective modification on methionine residues by one-pot O- and N-transfer reaction, generating sulfoximine-modified peptides with near-perfect conversion within 10 min. Moreover, the great tolerance to other natural amino acids has been demonstrated in reactions with various peptide substrates. To demonstrate the generality of this protocol, we have modified natural peptides and obtained sulfoximination products with high conversion rates. This methodology provides a novel strategy as the expansion of the methionine-based peptide functionalization toolbox.


Assuntos
Metionina , Proteínas , Metionina/química , Metionina/metabolismo , Proteínas/química , Peptídeos/química , Racemetionina/metabolismo , Estresse Oxidativo
4.
Proc Natl Acad Sci U S A ; 118(26)2021 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-34172566

RESUMO

The spread of pathological α-synuclein (α-syn) is a crucial event in the progression of Parkinson's disease (PD). Cell surface receptors such as lymphocyte activation gene 3 (LAG3) and amyloid precursor-like protein 1 (APLP1) can preferentially bind α-syn in the amyloid over monomeric state to initiate cell-to-cell transmission. However, the molecular mechanism underlying this selective binding is unknown. Here, we perform an array of biophysical experiments and reveal that LAG3 D1 and APLP1 E1 domains commonly use an alkaline surface to bind the acidic C terminus, especially residues 118 to 140, of α-syn. The formation of amyloid fibrils not only can disrupt the intramolecular interactions between the C terminus and the amyloid-forming core of α-syn but can also condense the C terminus on fibril surface, which remarkably increase the binding affinity of α-syn to the receptors. Based on this mechanism, we find that phosphorylation at serine 129 (pS129), a hallmark modification of pathological α-syn, can further enhance the interaction between α-syn fibrils and the receptors. This finding is further confirmed by the higher efficiency of pS129 fibrils in cellular internalization, seeding, and inducing PD-like α-syn pathology in transgenic mice. Our work illuminates the mechanistic understanding on the spread of pathological α-syn and provides structural information for therapeutic targeting on the interaction of α-syn fibrils and receptors as a potential treatment for PD.


Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Amiloide/metabolismo , Antígenos CD/metabolismo , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , alfa-Sinucleína/metabolismo , Animais , Linhagem Celular Tumoral , Endocitose , Humanos , Camundongos , Degeneração Neural/patologia , Neurônios/metabolismo , Fosforilação , Fosfosserina/metabolismo , Ligação Proteica , Eletricidade Estática , alfa-Sinucleína/química , alfa-Sinucleína/toxicidade , Proteína do Gene 3 de Ativação de Linfócitos
5.
J Pept Sci ; 27(1): e3286, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32945039

RESUMO

Chemical protein modifications facilitate the investigation of natural posttranslational protein modifications and allow the design of proteins with new functions. Proteins can be modified at a late stage on amino acid side chains by chemical methods. The indole moiety of tryptophan residues is an emerging target of such chemical modification strategies because of its unique reactivity and low abundance. This review provides an overview of the recently developed methods of tryptophan modification at the peptide and protein levels.


Assuntos
Peptídeos/química , Proteínas/química , Triptofano/química
6.
Chem Commun (Camb) ; 56(83): 12632-12635, 2020 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-32960198

RESUMO

We developed a late-stage modification strategy by a phospha-Michael addition reaction between various functional phosphines and unprotected dehydroalanine (Dha) peptides and proteins under mild conditions. This strategy was applied to generate a staple peptide to enhance its cell membrane penetrability, and it was also able to regulate α-synuclein aggregation properties and morphological characteristics with the addition of different charges.


Assuntos
Peptídeos/química , Fosfinas/química , Fluoresceína/química , Humanos , Células MCF-7 , Microscopia Confocal , Peptídeos/metabolismo , Agregados Proteicos , alfa-Sinucleína/química , alfa-Sinucleína/metabolismo
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