RESUMO
PURPOSE: There is growing interest in seeking pharmacological activation of neurolysin (Nln) for stroke treatment. Discovery of central nervous system drugs remains challenging due to the protection of the blood-brain barrier (BBB). The previously reported peptidomimetic Nln activators display unsatisfactory BBB penetration. Herein, we investigate the next generation of non-peptidomimetic Nln activators with high BBB permeability. METHODS: A BBB-mimicking model was used to evaluate their in vitro BBB permeability. Protein binding, metabolic stability, and efflux assays were performed to determine their unbound fraction, half-lives in plasma and brains, and dependence of BBB transporter P-glycoprotein (P-gp). The in vivo pharmacokinetic profiles were elucidated in healthy and stroke mice. RESULTS: Compounds KS52 and KS73 out of this generation exhibit improved peptidase activity and BBB permeability compared to the endogenous activator and previous peptidomimetic activators. They show reasonable plasma and brain protein binding, improved metabolic stability, and independence of P-gp-mediated efflux. In healthy animals, they rapidly distribute into brains and reach peak levels of 18.69% and 12.10% injected dose (ID)/ml at 10 min. After 4 h, their total brain concentrations remain 7.78 and 12.34 times higher than their A50(minimal concentration required for enhancing 50% peptidase activity). Moreover, the ipsilateral hemispheres of stroke animals show comparable uptake to the corresponding contralateral hemispheres and healthy brains. CONCLUSIONS: This study provides essential details about the pharmacokinetic properties of a new generation of potent non-peptidomimetic Nln activators with high BBB permeability and warrants the future development of these agents as potential neuroprotective pharmaceutics for stroke treatment.
Assuntos
Peptidomiméticos , Acidente Vascular Cerebral , Camundongos , Animais , Barreira Hematoencefálica/metabolismo , Peptidomiméticos/metabolismo , Metaloendopeptidases/metabolismo , Acidente Vascular Cerebral/tratamento farmacológico , PermeabilidadeRESUMO
In organic chemistry, the use of deuterium exchange as a tool to study the mechanism of chemical reaction has been well explored. Since two decades, the research focus on deuterated bioactive molecules has been gaining attention for investigating the therapeutic potential of deuterium replacement in a chemical structure. Recently, Food Drug Administration (FDA) approved the first deuterium-labeled drug "deutetrabenazine", and notified the deuterated drugs as new chemical entities (NCEs). Henceforth, the deuterium substitution driven structure activity relationship, preclinical pharmacokinetics, and toxicity studies were much initiated. Deuteration of a bioactive molecule often results in improved therapeutic efficacy due to the altered pharmacokinetic profile. This review provides a conceptual framework on the importance of deuterium atom in chemical structure of a drug, and its biological value in improved physiochemical properties, pharmacokinetics, biological target interaction, diagnosis, and toxicity. In addition, this review concisely updated the recent deuteration methods, chemical stability, challenges in drug development, deuterium-based imaging in diagnosis, and selected synthetic scheme of deuterated molecules.
Assuntos
Desenvolvimento de Medicamentos , Deutério/química , Preparações Farmacêuticas/química , Relação Estrutura-AtividadeRESUMO
Inhibition of specific carbonic anhydrase (CA) enzymes is a validated strategy for the development of agents to target cancer. The CA isoforms IX and XII are overexpressed in various human solid tumors wherein they play a critical role in regulating extracellular tumor acidification, proliferation, and progression. A series of novel sulfonamides based on the coumarin scaffold were designed, synthesized and characterized as potent and selective CA inhibitors. Selected compounds show significant activity and selectivity over CA I and CA II to target the tumor-associated CA IX and CA XII with high inhibition activity at the single digit nanomolar level. Twelve compounds were identified to be more potent compared with acetazolamide (AAZ) control to inhibit CA IX while one was also more potent than AAZ to inhibit CA XII. Compound 18f (Ki's = 955 nM, 515 nM, 21 nM and 5 nM for CA's I, II, IX, and XII, respectively) is highlighted as a novel CA IX and XII inhibitor for further development.
Assuntos
Cumarínicos , Neoplasias , Humanos , Anidrase Carbônica IX/metabolismo , Estrutura Molecular , Relação Estrutura-Atividade , Cumarínicos/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Acetazolamida/farmacologiaRESUMO
Modulating peptidase neurolysin (Nln) has been identified as a potential cerebroprotective target for the development of therapeutics for ischemic stroke. Continued structure-activity relationship studies on peptidomimetic small molecule activators of Nln bearing electron-donating and electron- withdrawing functionalized phenyls are explored. Incorporation of fluorine or trifluoromethyl groups produces Nln activators with enhanced A50, while methoxy substitution produces derivatives with enhanced Amax. Selected activators containing methoxy or trifluoromethyl substitution are selective for Nln over related peptidases and possess increased blood-brain barrier penetrability than initial hits.
Assuntos
Peptidomiméticos , Metaloendopeptidases/metabolismo , Peptídeo Hidrolases/metabolismo , Peptidomiméticos/farmacologia , Relação Estrutura-AtividadeRESUMO
A novel series of 4-anilinoquinazoline analogues, DW (1-10), were evaluated for anticancer efficacy in human breast cancer (BT-20) and human colorectal cancer (CRC) cell lines (HCT116, HT29, and SW620). The compound, DW-8, had the highest anticancer efficacy and selectivity in the colorectal cancer cell lines, HCT116, HT29, and SW620, with IC50 values of 8.50 ± 2.53 µM, 5.80 ± 0.92 µM, and 6.15 ± 0.37 µM, respectively, compared to the non-cancerous colon cell line, CRL1459, with an IC50 of 14.05 ± 0.37 µM. The selectivity index of DW-8 was >2-fold in colon cancer cells incubated with vehicle. We further determined the mechanisms of cell death induced by DW-8 in SW620 CRC cancer cells. DW-8 (10 and 30 µM) induced apoptosis by (1) producing cell cycle arrest at the G2 phase; (2) activating the intrinsic apoptotic pathway, as indicated by the activation of caspase-9 and the executioner caspases-3 and 7; (3) nuclear fragmentation and (4) increasing the levels of reactive oxygen species (ROS). Overall, our results suggest that DW-8 may represent a suitable lead for developing novel compounds to treat CRC.
Assuntos
Apoptose/efeitos dos fármacos , Neoplasias do Colo , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Células HCT116 , Células HT29 , HumanosRESUMO
Carbazole based novel multifunctional agents has been rationally designed and synthesized as potential anti-Alzheimer agents. Multi-functional activity of these derivatives have been assessed by performing various in-vitro assays and these compounds appeared to be potent AChE inhibitors, Aß aggregation inhibitors, anti-oxidant and neuroprotective agents. Among the entire series, MT-1 and MT-6 were most potent multifunctional agents which displayed effective and selective AChE inhibition, Aß disaggregation, anti-oxidant and metal chelation action. Neuroprotective activity of MT-6 has been examined against H2O2 induced toxicity in SHSY-5Y cells and they have shown effective neuroprotection. Additionally, MT-6 did not display any significant toxicity in SHSY-5Y cells, indicating its non-toxic nature. Molecular docking and MD simulation studies have been also performed to explore molecular level interaction with AChE and Aß. Finally, MT-6 was evaluated against scopolamine induced dementia model of mice and this compound actively improved memory deficit and cognition impairment in scopolamine treated mice. Thus, novel carbazole derivative MT-6 has been explored as an effective and safe multifunctional agent against AD and this molecule may be used as a suitable lead for development of effective anti-Alzheimer agents in future.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Carbazóis/uso terapêutico , Desenho de Fármacos , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Linhagem Celular , Simulação por Computador , Humanos , Peróxido de Hidrogênio/farmacologia , Técnicas In Vitro , Microscopia Eletrônica de Transmissão , Simulação de Acoplamento Molecular , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismoRESUMO
New chrysin-De-allyl-Pac-1 hybrid analogues, tethered with variable heterocyclic systems (4a-4o), were rationally designed and synthesized. The target compounds were screened for in vitro antiproliferative efficacy in the triple-negative breast cancer (TNBC) cell line, MDA-MB-231, and normal human mammary epithelial cells (HMECs). Two compounds, 4g and 4i, had the highest efficacy and selectivity towards MDA-MB-231 cells, and thus, were further evaluated by mechanistic experiments. The results indicated that both compounds 4g and 4i induced apoptosis by (1) inducing cell cycle arrest at the G2 phase in MDA-MB-231 cells, and (2) activating the intrinsic apoptotic pathways in a concentration-dependent manner. Physicochemical characterizations of these compounds suggested that they can be further optimized as potential anticancer compounds for TNBC cells. Overall, our results suggest that 4g and 4i could be suitable leads for developing novel compounds to treat TNBC.
Assuntos
Compostos Alílicos/química , Antineoplásicos/farmacologia , Flavonoides/química , Hidrazonas/química , Piperazinas/química , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Antineoplásicos/química , Apoptose , Ciclo Celular , Movimento Celular , Proliferação de Células , Feminino , Humanos , Neoplasias de Mama Triplo Negativas/patologia , Células Tumorais CultivadasRESUMO
A series of novel 2-(4-(4-substituted piperazin-1-yl)benzylidene)hydrazinecarboxamide derivatives has been successfully designed and synthesized to evaluate their potential as carbonic anhydrase (CA) inhibitors. The inhibitory potential of synthesized compounds against human CAI and CAII was evaluated. Compounds 3a-n exhibited [Formula: see text] values between [Formula: see text] against CAI and [Formula: see text] against CAII. Compound 3g was the most active inhibitor, with an [Formula: see text] value of [Formula: see text] against CAII. Molecular docking studies of compound 3g with CAII showed this compound fits nicely in the active site of CAII and it interacts with the zinc ion ([Formula: see text]) along with three histidine residues in the active site. Molecular dynamics simulation studies of compound 3g complexed with CAII also showed essential interactions which were maintained up to 40 ns of simulation. In vivo sub-acute toxicity study using 3g (300 mg/kg) was found non-toxic in adult Wistar rats.
Assuntos
Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/farmacologia , Simulação por Computador , Desenho de Fármacos , Hidrazinas/síntese química , Hidrazinas/farmacologia , Animais , Anidrase Carbônica I/antagonistas & inibidores , Anidrase Carbônica I/química , Anidrase Carbônica I/metabolismo , Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica II/química , Anidrase Carbônica II/metabolismo , Inibidores da Anidrase Carbônica/metabolismo , Inibidores da Anidrase Carbônica/toxicidade , Domínio Catalítico , Técnicas de Química Sintética , Humanos , Hidrazinas/metabolismo , Hidrazinas/toxicidade , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ratos , Ratos WistarRESUMO
A series of novel 2-(4-(4-substituted piperazin-1-yl)benzylidene)-1H-indene-1,3(2H)-diones were designed, synthesized and appraised as multifunctional anti-Alzheimer agents. In vitro studies of compounds 27-38 showed that these compounds exhibit moderate to excellent AChE, BuChE and Aß aggregation inhibitory activity. Notably, compounds 34 and 38 appeared as most active multifunctional agents in the entire series and exhibited excellent inhibition against AChE (IC50=0.048µM: 34; 0.036µM: 38), Aß aggregation (max% inhibition 82.2%, IC50=9.2µM: 34; max% inhibition 80.9%, IC50=10.11µM: 38) and displayed significant antioxidant potential in ORAC-FL assay. Both compounds also successfully diminished H2O2 induced oxidative stress in SH-SY5Y cells. Fascinatingly, compounds 34 and 38 showed admirable neuroprotective effects against H2O2 and Aß induced toxicity in SH-SY5Y cells. Additionally, both derivatives showed no considerable toxicity in neuronal cell viability assay and represented drug likeness properties in the primarily pharmacokinetics study. All these results together, propelled out that compounds 34 and 38 might serve as promising multi-functional lead candidates for treatment of AD in the future.
Assuntos
Doença de Alzheimer/prevenção & controle , Peptídeos beta-Amiloides/antagonistas & inibidores , Antioxidantes/farmacologia , Inibidores da Colinesterase/farmacologia , Indanos/química , Indanos/farmacologia , Fármacos Neuroprotetores/farmacologia , Linhagem Celular , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Peróxido de Hidrogênio/toxicidade , Indanos/síntese química , Cinética , Microscopia Eletrônica de TransmissãoRESUMO
A series of N-(5-methyl-isoxazol-3-yl/1,3,4-thiadiazol-2-yl)-4-(3-substitutedphenylureido) benzenesulfonamide derivatives has been designed, synthesized and screened for their in vitro human carbonic anhydrase (hCA; EC 4.2.1.1) inhibition potential. These newly synthesized sulfonamide compounds were assessed against isoforms hCA I, II, VII and XII, with acetazolamide (AAZ) as a reference compound. The majority of these compounds were found quite weak inhibitor against all tested isoforms. Compound 15 showed a modest inhibition potency against hCA I (Ki = 73.7 µM) and hCA VII (Ki = 85.8 µM). Compounds 19 and 25 exhibited hCA II inhibition with Ki values of 96.0 µM and 87.8 µM, respectively. The results of the present study suggest that, although the synthesized derivatives have weak inhibitory potential towards all investigated isoforms, some of them may serve as lead molecules for the further development of selective inhibitors incorporating secondary sulfonamide functionalities, a class of inhibitors for which the inhibition mechanism is poorly understood.
Assuntos
Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Desenho de Fármacos , Sulfonamidas/farmacologia , Anidrase Carbônica I/antagonistas & inibidores , Anidrase Carbônica I/metabolismo , Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica II/metabolismo , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , BenzenossulfonamidasRESUMO
TRPV4 is involved in several physiological and sensory functions as well as with several diseases and genetic disorders, though the molecular mechanisms for these are unclear. In this work we have analyzed molecular evolution and structure-function relationship of TRPV4 using sequences from different species. TRPV4 has evolved during early vertebrate origin (450million years). Synteny analysis confirms that TRPV4 has coevolved with two enzymes involved in sterol biosynthesis, namely MVK and GLTP. Cholesterol-recognizing motifs are present within highly conserved TM4-Loop4-TM5 region of TRPV4. TRPV4 is present in lipid raft where it co-localizes with Caveolin1 and Filipin. TM4-Loop4-TM5 region as well as Loop4 alone can physically interact with cholesterol, its precursor mevalonate and derivatives such as stigmasterol and aldosterone. Mobility of TRPV4-GFP depends on membrane cholesterol level. Molecular evolution of TRPV4 shared striking parallelism with the cholesterol bio-synthesis pathways at the genetic, molecular and metabolic levels. We conclude that interaction with sterols and cholesterol-dependent membrane dynamics have influence on TRPV4 function. These results may have importance on TRPV4-medaited cellular functions and pathophysiology.
Assuntos
Membrana Celular/metabolismo , Colesterol/metabolismo , Microdomínios da Membrana/metabolismo , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismo , Motivos de Aminoácidos , Sequência de Aminoácidos , Animais , Caveolina 1/metabolismo , Biologia Computacional , Bases de Dados de Proteínas , Evolução Molecular , Filipina/metabolismo , Humanos , Dados de Sequência Molecular , Ligação Proteica , Estrutura Terciária de Proteína , Homologia de Sequência de Aminoácidos , SoftwareRESUMO
A series of alkyl/aryl/heteroaryl piperazine derivatives (37-54) were designed and synthesized as potential anticonvulsant agents. The target compounds are endowed with satisfactory physicochemical as well as pharmacokinetic properties. The synthesized compounds were screened for their in vivo anticonvulsant activity in maximal electroshock (MES) and subcutaneous pentylenetetrazole (sc-PTZ) seizure tests. Further, neurotoxicity evaluation was carried out using rotarod method. Structure activity relationship studies showed that compounds possessing aromatic group at the piperazine ring displayed potent anticonvulsant activity. Majority of the compounds showed anti-MES activity whereas compounds 39, 41, 42, 43, 44, 50, 52, and 53 exhibited anticonvulsant activity in both seizure tests. All the compounds except 42, 46, 47, and 50 did not show neurotoxicity. The most active derivative, 45 demonstrated potent anticonvulsant activity in MES test at the dose of 30mg/kg (0.5h) and 100mg/kg (4h) and also delivered excellent protection in sc-PTZ test (100mg/kg) at both time intervals. Therefore, compound 45 was further assessed in PTZ-kindling model of epilepsy which is widely used model for studying epileptogenesis. This compound was effective in delaying onset of PTZ-evoked seizures at the dose of 5mg/kg in kindled animals and significantly reduced oxidative stress better than standard drug phenobarbital (PB). In result, compound 45 emerged as a most potent and safer anticonvulsant lead molecule.
Assuntos
Anticonvulsivantes/química , Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Piperazinas/química , Piperazinas/uso terapêutico , Convulsões/tratamento farmacológico , Animais , Anticonvulsivantes/síntese química , Carbamatos/síntese química , Carbamatos/química , Carbamatos/uso terapêutico , Desenho de Fármacos , Eletrochoque , Epilepsia/induzido quimicamente , Camundongos , Pentilenotetrazol , Piperazina , Piperazinas/síntese química , Convulsões/induzido quimicamenteRESUMO
While effects of different steroids on the gene expression and regulation are well established, it is proven that steroids can also exert rapid non-genomic actions in several tissues and cells. In most cases, these non-genomic rapid effects of steroids are actually due to intracellular mobilization of Ca(2+)- and other ions suggesting that Ca(2+) channels are involved in such effects. Transient Receptor Potential (TRP) ion channels or TRPs are the largest group of non-selective and polymodal ion channels which cause Ca(2+)-influx in response to different physical and chemical stimuli. While non-genomic actions of different steroids on different ion channels have been established to some extent, involvement of TRPs in such functions is largely unexplored. In this review, we critically analyze the literature and summarize how different steroids as well as their metabolic precursors and derivatives can exert non-genomic effects by acting on different TRPs qualitatively and/or quantitatively. Such effects have physiological repercussion on systems such as in sperm cells, immune cells, bone cells, neuronal cells and many others. Different TRPs are also endogenously expressed in diverse steroid-producing tissues and thus may have importance in steroid synthesis as well, a process which is tightly controlled by the intracellular Ca(2+) concentrations. Tissue and cell-specific expression of TRP channels are also regulated by different steroids. Understanding of the crosstalk between TRP channels and different steroids may have strong significance in physiological, endocrinological and pharmacological context and in future these compounds can also be used as potential biomedicine.
Assuntos
Cálcio/metabolismo , Esteroides/uso terapêutico , Canais de Potencial de Receptor Transitório/fisiologia , Humanos , Esteroides/metabolismo , Canais de Potencial de Receptor Transitório/metabolismoRESUMO
Iron-based compounds possess the capability of inducing cell death due to their reactivity with oxidant molecules, but their specificity towards cancer cells and the mechanism of action are hitherto less investigated. A Fe(salen)Cl derivative has been synthesized that remains active in monomer form. The efficacy of this compound as an anti-tumor agent has been investigated in mouse and human leukemia cell lines. Fe(salen)Cl induces cell death specifically in tumor cells and not in primary cells. Mouse and human T-cell leukemia cell lines, EL4 and Jurkat cells are found to be susceptible to Fe(salen)Cl and undergo apoptosis, but normal mouse spleen cells and human peripheral blood mononuclear cells (PBMC) remain largely unaffected by Fe(salen)Cl. Fe(salen)Cl treated tumor cells show significantly higher expression level of cytochrome c that might have triggered the cascade of reactions leading to apoptosis in cancer cells. A significant loss of mitochondrial membrane potential upon Fe(salen)Cl treatment suggests that Fe(salen)Cl induces apoptosis by disrupting mitochondrial membrane potential and homeostasis, leading to cytotoxity. We also established that apoptosis in the Fe(salen)Cl-treated tumor cells is mediated through caspase-dependent pathway. This is the first report demonstrating that Fe(salen)Cl can specifically target the tumor cells, leaving the primary cells least affected, indicating an excellent potential for this compound to emerge as a next-generation anti-tumor drug.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Cloretos/química , Cloretos/farmacologia , Etilenodiaminas/química , Compostos Férricos/química , Compostos Férricos/farmacologia , Clorometilcetonas de Aminoácidos/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Fator Apoptótico 1 Ativador de Proteases/metabolismo , Linhagem Celular , Cloretos/síntese química , Citocromos c/metabolismo , Regulação para Baixo/efeitos dos fármacos , Etilenodiaminas/síntese química , Etilenodiaminas/farmacologia , Compostos Férricos/síntese química , Humanos , Células Jurkat , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Regulação para Cima/efeitos dos fármacos , Proteína de Morte Celular Associada a bcl/metabolismoRESUMO
Dendrites are tree-like structures with tiny spines specialized to receive excitatory synaptic transmission. Spino-dendritic plasticity, driven by neural activity, underlies the maintenance of neuronal connections crucial for proper circuit function. Abnormalities in dendritic morphology are frequently seen in epilepsy. However, the exact etiology or functional implications are not yet known. Therefore, to better comprehend the structure-function significance of this dendritic pathology in epilepsy, it is necessary to identify the common spino-dendritic disturbances present in both human and experimental models. Here, we describe the dendritic and spine structural profiles found across human refractory epilepsy as well as in animal models of developmental, acquired, and genetic epilepsies.
RESUMO
HLA-A*33:33:02 differs from HLA-A*33:33:01 by one synonymous nucleotide change C>T in exon 3 (TCC>TCT).
Assuntos
Alelos , Éxons , Antígenos HLA-A , Humanos , Antígenos HLA-A/genética , Índia , Sequência de Bases , Teste de Histocompatibilidade , Análise de Sequência de DNA , Masculino , Polimorfismo de Nucleotídeo Único , FemininoRESUMO
HLA-C*17:78 differs from HLA-C*17:03:01:03 by one nucleotide change C>T in exon 3 (GCG>GTG).
Assuntos
Alelos , Sequência de Bases , Éxons , Antígenos HLA-C , Humanos , Antígenos HLA-C/genética , Índia , Teste de Histocompatibilidade , Análise de Sequência de DNA , Alinhamento de Sequência , Polimorfismo de Nucleotídeo Único , CódonRESUMO
HLA-B*40:06:01:18 differs from HLA-B*40:06:01:02 by one nucleotide change in the 5'UTR (T > C).
Assuntos
Povo Asiático , Genes MHC Classe I , Humanos , Alelos , Regiões 5' não Traduzidas , Antígenos HLA-B/genéticaRESUMO
Asymmetric transport of cargo across axonal branches is a field of active research. Mechanisms contributing to preferential cargo transport along specific branches in vivo in wild type neurons are poorly understood. We find that anterograde synaptic vesicles preferentially enter the synaptic branch or pause at the branch point in Caenorhabditis elegans Posterior Lateral Mechanosensory neurons. The synaptic vesicle anterograde kinesin motor UNC-104/KIF1A regulates this vesicle behavior at the branch point. Reduced levels of functional UNC-104 cause vesicles to predominantly pause at the branch point and lose their preference for turning into the synaptic branch. SAM-4/Myrlysin, which aids in recruitment/activation of UNC-104 on synaptic vesicles, regulates vesicle behavior at the branch point similar to UNC-104. Increasing the levels of UNC-104 increases the preference of vesicles to go straight toward the asynaptic end. This suggests that the neuron optimizes UNC-104 levels on the cargo surface to maximize the fraction of vesicles entering the branch and minimize the fraction going to the asynaptic end.
Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Cinesinas , Proteínas do Tecido Nervoso , Vesículas Sinápticas , Animais , Vesículas Sinápticas/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/genética , Cinesinas/metabolismo , Cinesinas/genética , Neurônios/metabolismoRESUMO
To combat multifactorial refractory diseases, such as cancer, cardiovascular, and neurodegenerative diseases, multitarget drugs have become an emerging area of research aimed at 'synthetic lethality' (SL) relationships associated with drug-resistance mechanisms. In this review, we discuss the in silico design of dual and triple-targeted ligands, strategies by which specific 'warhead' groups are incorporated into a parent compound or scaffold with primary inhibitory activity against one target to develop one small molecule that inhibits two or three molecular targets in an effort to increase potency against multifactorial diseases. We also discuss the analytical exploration of structure-activity relationships (SARs), physicochemical properties, polypharmacology, scaffold feature extraction of US Food and Drug Administration (FDA)-approved multikinase inhibitors (MKIs), and updates regarding the clinical status of dual-targeted chemotypes.