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1.
ACS Appl Bio Mater ; 7(6): 4142-4161, 2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38770768

RESUMO

The emergence of antimicrobial resistance, exemplified by methicillin-resistant Staphylococcus aureus (MRSA), poses a grave threat to public health globally. Over time, MRSA has evolved resistance to multiple antibiotics, challenging conventional treatment strategies. The relentless adaptability of MRSA underscores the urgent need for innovative and targeted antimicrobial approaches to combat this resilient pathogen. Ancient knowledge and practices, along with scientific evidence, have established that metallic copper, and its organic coordination complexes can act as potential antibacterial substances. In search of a smart and effective antimicrobial against MRSA, we designed, synthesized, and characterized a bidentate copper(II) ligand complex (SG-Cu) utilizing a comprehensive array of analytical techniques, including ESI-MS, elemental analysis, X-ray photoelectron spectroscopy, electron paramagnetic resonance spectroscopy, and others. Antibacterial efficacy and mechanism of action of the complex were assessed through bacterial growth analyses, bacterial membrane perturbation assays, ROS elicitation assays, and field emission scanning electron microscopy. SG-Cu was found to maintain robust biocompatibility against the mammalian cell lines HEK-293, WI-38, and NIH/3T3. Remarkably, SG-Cu demonstrated significant biofilm disruptive tendency evidenced by the retardation of sliding motility, reduction in slime production, reduction in biofilm viability, and enhanced biofilm eradication, both in vitro and in urinary catheters. In vivo studies on murine excisional wounds, with SG-Cu impregnated in a palmitic acid conjugated NAVSIQ hexapeptide (PA-NV) hydrogel, revealed the sustained release of SG-Cu from the gel matrix, facilitating accelerated wound healing and effective wound disinfection. This multifaceted investigation highlights the potential of SG-Cu as a versatile option for combating MRSA infections and promoting wound healing, solidifying its claim to be developed into a viable therapeutic.


Assuntos
Antibacterianos , Cobre , Hidrogéis , Staphylococcus aureus Resistente à Meticilina , Testes de Sensibilidade Microbiana , Quinolinas , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Cobre/química , Cobre/farmacologia , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Humanos , Hidrogéis/química , Hidrogéis/farmacologia , Camundongos , Animais , Quinolinas/química , Quinolinas/farmacologia , Ligantes , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Materiais Biocompatíveis/síntese química , Biofilmes/efeitos dos fármacos , Tamanho da Partícula , Cicatrização/efeitos dos fármacos , Teste de Materiais , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/administração & dosagem , Sobrevivência Celular/efeitos dos fármacos , Estrutura Molecular
2.
J Med Chem ; 67(11): 9260-9276, 2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38771158

RESUMO

Duchenne muscular dystrophy (DMD) is a fatal muscle-wasting disease caused by the absence of a dystrophin protein. Elevating utrophin, a dystrophin paralogue, offers an alternative therapeutic strategy for treating DMD, irrespective of the mutation type. Herein, we report the design and synthesis of novel quinazoline and quinoline-based small molecules as potent utrophin modulators screened via high throughput In-Cell ELISA in C2C12 cells. Remarkably, lead molecule SG-02, identified from a library of 70 molecules, upregulates utrophin 2.7-fold at 800 nM in a dose-dependent manner, marking the highest upregulation within the nanomolar range. SG-02's efficacy was further validated through DMD patient-derived cells, demonstrating a significant 2.3-fold utrophin expression. Mechanistically, SG-02 functions as an AhR antagonist, with excellent binding affinity (Kd = 41.68 nM). SG-02 also enhances myogenesis, as indicated by an increased MyHC expression. ADME evaluation supports SG-02's oral bioavailability. Overall, SG-02 holds promise for addressing the global DMD population.


Assuntos
Distrofia Muscular de Duchenne , Quinazolinas , Quinolinas , Receptores de Hidrocarboneto Arílico , Utrofina , Distrofia Muscular de Duchenne/tratamento farmacológico , Distrofia Muscular de Duchenne/metabolismo , Utrofina/metabolismo , Quinolinas/farmacologia , Quinolinas/química , Humanos , Receptores de Hidrocarboneto Arílico/metabolismo , Receptores de Hidrocarboneto Arílico/antagonistas & inibidores , Animais , Camundongos , Quinazolinas/farmacologia , Quinazolinas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/química , Descoberta de Drogas , Regulação para Cima/efeitos dos fármacos , Linhagem Celular , Relação Estrutura-Atividade , Fatores de Transcrição Hélice-Alça-Hélice Básicos/antagonistas & inibidores , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo
3.
ACS Infect Dis ; 10(4): 1267-1285, 2024 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-38442370

RESUMO

The escalation of bacterial resistance against existing therapeutic antimicrobials has reached a critical peak, leading to the rapid emergence of multidrug-resistant strains. Stringent pathways in novel drug discovery hinder our progress in this survival race. A promising approach to combat emerging antibiotic resistance involves enhancing conventional ineffective antimicrobials using low-toxicity small molecule adjuvants. Recent research interest lies in weak membrane-perturbing agents with unique cyclic hydrophobic components, addressing a significant gap in antimicrobial drug exploration. Our study demonstrates that quinoline-based amphipathic small molecules, SG-B-52 and SG-B-22, significantly reduce MICs of selected beta-lactam antibiotics (ampicillin and amoxicillin) against lethal methicillin-resistant Staphylococcus aureus (MRSA). Mechanistically, membrane perturbation, depolarization, and ROS generation drive cellular lysis and death. These molecules display minimal in vitro and in vivo toxicity, showcased through hemolysis assays, cell cytotoxicity analysis, and studies on albino Wistar rats. SG-B-52 exhibits impressive biofilm-clearing abilities against MRSA biofilms, proposing a strategy to enhance beta-lactam antibiosis and encouraging the development of potent antimicrobial potentiators.


Assuntos
Anti-Infecciosos , Staphylococcus aureus Resistente à Meticilina , Quinolinas , beta-Lactamas/farmacologia , beta-Lactamas/uso terapêutico , Sinergismo Farmacológico , Anti-Infecciosos/farmacologia , Quinolinas/farmacologia
4.
J Med Chem ; 66(16): 11555-11572, 2023 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-37566805

RESUMO

Antimicrobial cationic peptides are intriguing and propitious antibiotics for the future, even against multidrug-resistant superbugs. Venoms serve as a source of cutting-edge therapeutics and innovative, unexplored medicines. In this study, a novel cationic peptide library consisting of seven sequences was designed and synthesized from the snake venom cathelicidin, batroxicidin (BatxC), with the inclusion of the FLPII motif at the N-terminus. SP1V3_1 demonstrated exceptional antibacterial effectiveness against Escherichia coli, methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, and Klebsiella pneumoniae and destroyed the bacteria by depolarizing, rupturing, and permeabilizing their membranes, as evident from fluorescence assays, atomic force microscopy, and scanning electron microscopy. SP1V3_1 was observed to modulate the immune response in LPS-elicited U937 cells and exhibited good antibiofilm activity against MRSA and K. pneumoniae. The peptide promoted wound healing and disinfection in the murine model. The study demonstrated that SP1V3_1 is an exciting peptide lead and may be explored further for the development of better therapeutic peptides.


Assuntos
Anti-Infecciosos , Desinfetantes , Staphylococcus aureus Resistente à Meticilina , Camundongos , Animais , Testes de Sensibilidade Microbiana , Peptídeos Catiônicos Antimicrobianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/química , Antibacterianos/farmacologia , Cicatrização , Venenos de Serpentes , Escherichia coli
5.
ACS Chem Neurosci ; 14(2): 246-260, 2023 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-36583718

RESUMO

Amyloid-ß 42(Aß42), an enzymatically cleaved (1-42 amino acid long) toxic peptide remnant, has long been reported to play the key role in Alzheimer's disease (AD). Aß42 also plays the key role in the onset of other AD-related factors including hyperphosphorylation of tau protein that forms intracellular neurofibrillary tangles, imbalances in the function of the neurotransmitter acetylcholine, and even generation of reactive oxygen species (ROS), disrupting the cytoskeleton and homeostasis of the cell. To address these issues, researchers have tried to construct several strategies to target multiple aspects of the disease but failed to produce any clinically successful therapeutic molecules. In this article, we report a new peptoid called RA-1 that was designed and constructed from the hydrophobic stretch of the Aß42 peptide, 16KLVFFA21. This hydrophobic stretch is primarily responsible for the Aß42 peptide aggregation. Experimental study showed that the RA-1 peptoid is stable under proteolytic conditions, can stabilize the microtubule, and can inhibit the formation of toxic Aß42 aggregates by attenuating hydrophobic interactions between Aß42 monomers. Furthermore, results from various intracellular assays showed that RA-1 inhibits Aß42 fibril formation caused by the imbalance in AchE activity, reduces the production of cytotoxic reactive oxygen species (ROS), and promotes neurite outgrowth even in the toxic environment. Remarkably, we have also demonstrated that our peptoid has significant ability to improve the cognitive ability and memory impairment in in vivo rats exposed to AlCl3 and d-galactose (d-gal) dementia model. These findings are also validated with histological studies. Overall, our newly developed peptoid emerges as a multimodal potent therapeutic lead molecule against AD.


Assuntos
Doença de Alzheimer , Peptoides , Ratos , Animais , Doença de Alzheimer/metabolismo , Espécies Reativas de Oxigênio , Peptoides/farmacologia , Peptoides/metabolismo , Peptídeos beta-Amiloides/metabolismo , Fragmentos de Peptídeos/metabolismo , Interações Hidrofóbicas e Hidrofílicas
6.
ACS Chem Neurosci ; 11(3): 231-232, 2020 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-31939650

RESUMO

Chondroitin sulfate proteoglycans (CSPGs) are the most abundant components of glial scar formed after severe traumatic brain injury as well as spinal cord injury and play a crucial inhibitory role in axonal regeneration by selective contraction of filopodia of the growth cone of sprouting neurites. Healing of central nervous system (CNS) injury requires degradation of the glycosamine glycan backbone of CSPGs in order to reduce the inhibitory effect of the CSPG layer. The key focus of this Viewpoint is to address a few important regenerative approaches useful for overcoming the inhibitory barrier caused by chondroitin sulfate proteoglycans.


Assuntos
Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/metabolismo , Proteoglicanas de Sulfatos de Condroitina/metabolismo , Proteoglicanas de Sulfatos de Condroitina/farmacologia , Traumatismos da Medula Espinal/tratamento farmacológico , Animais , Humanos , Regeneração Nervosa/efeitos dos fármacos , Neuritos/efeitos dos fármacos , Neuritos/metabolismo , Pseudópodes/efeitos dos fármacos , Pseudópodes/metabolismo , Traumatismos da Medula Espinal/metabolismo
7.
RSC Adv ; 10(47): 28243-28266, 2020 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-35685027

RESUMO

The sudden ravaging outbreak of a novel coronavirus, or SARS-CoV-2, in terms of virulence, severity, and casualties has already overtaken previous versions of coronaviruses, like SARS CoV and MERS CoV. Originating from its epicenter in Wuhan, China, this mutated version of the influenza virus with its associated pandemic effects has engulfed the whole world with awful speed. In the midst of this bewildering situation, medical and scientific communities are on their toes to produce the potential vaccine-mediated eradication of this virus. Though the chances are really high, to date no such panacea has been reported. The time requirements for the onerous procedures of human trials for the successful clinical translation of any vaccine or potential therapeutics are also a major concern. In order to build some resistance against this massive pandemic, the repurposing of some earlier antiviral drugs has been done, along with the refurbishment of some immune-responsive alternative avenues, like monoclonal antibody mediated neutralization, interferon treatment, and plasma therapy. New drugs developed from the RBD domain of the virus spike protein and drugs targeting viral proteases are also undergoing further research and have shown potential from preliminary results. The sole purpose of this review article is to provide a brief collective overview of the recent status of therapeutics advances and approaches, and their current state of implementation for the management of COVID-19.

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