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1.
Front Bioeng Biotechnol ; 12: 1361966, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38410166

RESUMO

The mitochondria act as the main producers of reactive oxygen species (ROS) within cells. Elevated levels of ROS can activate the mitochondrial apoptotic pathway, leading to cell apoptosis. In this study, we devised a molecular prodrug named CTT2P, demonstrating notable efficacy in facilitating mitochondrial apoptosis. To develop nanomedicine, we enveloped CTT2P within bovine serum albumin (BSA), resulting in the formulation known as CTT2P@B. The molecular prodrug CTT2P is achieved by covalently conjugating mitochondrial targeting triphenylphosphine (PPh3), photosensitizer TPPOH2, ROS-sensitive thioketal (TK), and chemotherapeutic drug camptothecin (CPT). The prodrug, which is chemically bonded, prevents the escape of drugs while they circulate throughout the body, guaranteeing the coordinated dispersion of both medications inside the organism. Additionally, the concurrent integration of targeted photodynamic therapy and cascade chemotherapy synergistically enhances the therapeutic efficacy of pharmaceutical agents. Experimental results indicated that the covalently attached prodrug significantly mitigated CPT cytotoxicity under dark conditions. In contrast, TPPOH2, CTT2, CTT2P, and CTT2P@B nanoparticles exhibited increasing tumor cell-killing effects and suppressed tumor growth when exposed to light at 660 nm with an intensity of 280 mW cm-2. Consequently, this laser-triggered, mitochondria-targeted, combined photodynamic therapy and chemotherapy nano drug delivery system, adept at efficiently promoting mitochondrial apoptosis, presents a promising and innovative approach to cancer treatment.

2.
Bioorg Med Chem ; 76: 117083, 2022 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-36403413

RESUMO

Hybrid molecules containing small CD4 mimics and gp41-C-terminal heptad repeat (CHR)-related peptides have been developed. A YIR-821 derivative was adopted as a CD4 mimic, which inhibits the interaction of gp120 with CD4. SC-peptides, SC34 and SC22EK, were also used as CHR-related peptides, which inhibit the interaction between the N-terminal heptad repeat (NHR) and CHR and thereby membrane fusion. Therefore, these hybrid molecules have dual-targets of gp120 and gp41. In the synthesis of the hybrid molecules of CD4 mimic-SC-peptides with different lengths of linkers, two conjugating methods, Cu-catalyzed azide-alkyne cycloaddition and direct cysteine alkylation, were performed. The latter reaction caused simpler operation procedures and higher synthetic yields than the former. The synthesized hybrid molecules of CD4 mimic-SC22EK have significantly higher anti-HIV activity than each sole agent. The present data should be useful in the future design of anti-HIV agents as dual-target entry inhibitors.


Assuntos
Inibidores da Fusão de HIV , Inibidores da Fusão de HIV/farmacologia , Peptídeos/farmacologia
3.
Elife ; 112022 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-35119360

RESUMO

The centrosome composed of a pair of centrioles (mother and daughter) and pericentriolar material, and is mainly responsible for microtubule nucleation and anchorage in animal cells. The subdistal appendage (SDA) is a centriolar structure located at the mother centriole's subdistal region, and it functions in microtubule anchorage. However, the molecular composition and detailed structure of the SDA remain largely unknown. Here, we identified α-taxilin and γ-taxilin as new SDA components that form a complex via their coiled-coil domains and that serve as a new subgroup during SDA hierarchical assembly. The taxilins' SDA localization is dependent on ODF2, and α-taxilin recruits CEP170 to the SDA. Functional analyses suggest that α- and γ-taxilin are responsible for SDA structural integrity and centrosomal microtubule anchorage during interphase and for proper spindle orientation during metaphase. Our results shed light on the molecular components and functional understanding of the SDA hierarchical assembly and microtubule organization.


Assuntos
Centríolos/metabolismo , Proteínas de Choque Térmico/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Fenômenos Biológicos , Linhagem Celular , Linhagem Celular Tumoral , Humanos , Microtúbulos/metabolismo , Domínios Proteicos
4.
Bioorg Med Chem ; 30: 115923, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33316719

RESUMO

Several anti-HIV-1 peptides have previously been found among overlapping fragment peptide libraries that contain an octa-arginyl moiety and cover the whole sequence of an HIV-1 capsid (CA) protein. Several derivatives based on a potent CA fragment peptide CA-19L have been synthesized. CA-19L overlaps with the Helix 9 region of the CA protein, which could be important for oligomerization of the CA proteins. Derivatives of CA-19L in which several amino acid residues were added to the N- and C-termini according to the natural CA sequence, were synthesized and their anti-HIV activity was evaluated. Some potent compounds were found, and these potential new anti-HIV agents are expected to be useful as new tools for elucidation of CA functions.


Assuntos
Fármacos Anti-HIV/farmacologia , Proteínas do Capsídeo/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Fármacos Anti-HIV/química , Proteínas do Capsídeo/metabolismo , Relação Dose-Resposta a Droga , Humanos , Testes de Sensibilidade Microbiana , Conformação Proteica , Relação Estrutura-Atividade
5.
Bioorg Med Chem ; 28(11): 115488, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32305183

RESUMO

Utilizing overlapping fragment peptide libraries covering the whole sequence of an HIV-1 capsid (CA) protein with the addition of an octa-arginyl moiety, we had previously found several peptides with anti-HIV-1 activity. Herein, among these potent CA fragment peptides, CA-15L was examined because this peptide sequence overlaps with Helix 7, a helix region of the CA protein, which may be important for oligomerization of the CA proteins. A CA-15L surrogate with hydrophilic residues, and its derivatives, in which amino acid sequences are shifted toward the C-terminus by one or more residues, were synthesized and their anti-HIV activity was evaluated. In addition, its derivatives with substitution for the Ser149 residue were synthesized and their anti-HIV activity was evaluated because Ser149 might be phosphorylated in the step of degradation of CA protein oligomers. Several active compounds were found and might become new anti-HIV agents and new tools for elucidation of CA functions.


Assuntos
Fármacos Anti-HIV/farmacologia , Proteínas do Capsídeo/antagonistas & inibidores , HIV/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Fármacos Anti-HIV/química , Proteínas do Capsídeo/metabolismo , Relação Dose-Resposta a Droga , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Fragmentos de Peptídeos/química , Relação Estrutura-Atividade
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