RESUMEN
In 2019, the world faced a serious health challenge, the rapid spreading of a life-threatening viral pneumonia, coronavirus disease 2019 (COVID-19) caused by a betacoronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As of January 2022 WHO statistics shows more than 5.6 million death and about 350 million infection by SARS-CoV-2. One of the life threatening aspects of COVID-19 is secondary infections and reduced efficacy of antibiotics against them. Since the beginning of COVID-19 many researches have been done on identification, treatment, and vaccine development. Bacterial viruses (bacteriophages) could offer novel approaches to detect, treat and control COVID-19. Phage therapy and in particular using phage cocktails can be used to control or eliminate the bacterial pathogen as an alternative or complementary therapeutic agent. At the same time, phage interaction with the host immune system can regulate the inflammatory response. In addition, phage display and engineered synthetic phages can be utilized to develop new vaccines and antibodies, stimulate the immune system, and elicit a rapid and well-appropriate defense response. The emergence of SARS-CoV-2 new variants like delta and omicron has proved the urgent need for precise, efficient and novel approaches for vaccine development and virus detection techniques in which bacteriophages may be one of the plausible solutions. Therefore, phages with similar morphology and/or genetic content to that of coronaviruses can be used for ecological and epidemiological modeling of SARS-CoV-2 behavior and future generations of coronavirus, and in general new viral pathogens. This article is a comprehensive review/perspective of potential applications of bacteriophages in the fight against the present pandemic and the post-COVID era.
Asunto(s)
Bacteriófagos , COVID-19 , Neumonía Viral , COVID-19/terapia , Vacunas contra la COVID-19 , Humanos , SARS-CoV-2RESUMEN
Type II diabetes is a metabolic disease that has affected 460 million people around the globe and become a heavy burden on health care system. Diabetic patients suffer from hyperglycemia and hyperinsulinemia which can damage vital organs in body like heart, kidneys, eyes and nervous system. Different strategies have been introduced to control or lessen these diabetic complications in which one of the most promising approaches is the inhibition of intestinal sucrase-isomaltase (SI). Inhibition of this enzyme will block the release of glucose into bloodstream and lead to reduced postprandial hyperglycemia. MicroRNAs are small regulatory molecules that play critical roles in different cellular pathways and molecular mechanisms. It is proved that microRNAs have significant effects on cellular mechanisms involved in diabetes and can be used as biomarkers for diagnosis of this metabolic disease. Based on bioinformatics analysis miR-26a and miR-26b can interact with a conserved 3'-UTR region of SI mRNA which lead to a hypothesis that these miRs may have negative regulatory effect on this enzyme. In this study, we investigated the impact of high glucose conditions on expression of sucrase-isomaltase, miR-26a and miR-26b in caco-2â¯cell line. It is proved that in a simulated diabetic condition there is a reverse correlation between the expression pattern of these miRs and SI. QRT-PCR method was used to evaluate the expression of our target molecules. Interestingly, transfection of miR-26a and miR-26b in caco-2â¯cell line reduced the transcription of SI mRNA and decreased the sucrase and maltase activity of its active sites. To sum up, our results demonstrate the first evidence of the significant effect of miR-26a and miR-26b on SI expression and activity. We proved that these microRNAs may directly inhibit this enzyme and can be used as a new scaffold in search of finding novel treatments for type II diabetes.
Asunto(s)
Diabetes Mellitus Tipo 2/enzimología , Diabetes Mellitus Tipo 2/genética , Regulación hacia Abajo/genética , Regulación Enzimológica de la Expresión Génica , MicroARNs/metabolismo , Complejo Sacarasa-Isomaltasa/genética , Células CACO-2 , Regulación hacia Abajo/efectos de los fármacos , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Glucosa/farmacología , Humanos , MicroARNs/genética , Sacarasa/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/genéticaRESUMEN
The prevalence of diabetes mellitus has been incremented in the current century and the need for novel therapeutic compounds to treat this disease has been significantly increased. One of the most promising approaches is to inhibit intestinal alpha glucosidases. Based on our previous studies, four pyrimidine-fused heterocycles (PFH) were selected as they revealed satisfactory inhibitory action against mammalian α-glucosidase. The interaction of these compounds with both active domains of human maltase-glucoamylase (MGAM) and their effect on human Caco-2 cell line were investigated. The docking assessments suggested that binding properties of these ligands were almost similar to that of acarbose by establishing hydrogen bonds especially with Tyr1251 and Arg526 in both C-terminal and N-terminal MGAM, respectively. Also, these compounds indicated a stronger affinity for C-terminal of MGAM. L2 and L4 made tightly complexes with both terminals of MGAM which in turn revealed the importance of introducing pyrimidine scaffold and its hinge compartment. The results of molecular dynamics simulation analyses confirmed the docking data and showed deep penetration of L2 and L4 into the active site of MGAM. Based on cell cytotoxicity assessments, no significant cell death induction was observed. Hence, these functional MGAM inhibitors might be considered as new potential therapeutic compounds in treatment of diabetes and its complications.
Asunto(s)
Inhibidores de Glicósido Hidrolasas/farmacología , Pirimidinonas/farmacología , alfa-Glucosidasas/metabolismo , Acarbosa/química , Células CACO-2 , Dominio Catalítico , Inhibidores de Glicósido Hidrolasas/química , Inhibidores de Glicósido Hidrolasas/toxicidad , Compuestos Heterocíclicos con 3 Anillos/química , Compuestos Heterocíclicos con 3 Anillos/farmacología , Compuestos Heterocíclicos con 3 Anillos/toxicidad , Humanos , Enlace de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Ligandos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Estructura Molecular , Pirimidinonas/química , Pirimidinonas/toxicidad , alfa-Glucosidasas/químicaRESUMEN
A vast research has been conducted to find suitable and safe carriers for vital and pH-sensitive drugs including antibiotics. This article reports the use of easily accessible and abundant purified beta-lactoglobulin (ß-LG) protein as the potential carrier of widely used Kanamycin (Kana) and Ciprofloxacin (Cip) antibiotics. Spectroscopic techniques (Fluorescence, UV-vis, Circular Dichroism) combined with molecular docking were used to determine the binding mechanism of these drugs. Fluorescence studies showed moderate binding affinity with the calculated binding constants KCip = 60.1 (±0.2) × 103 M-1 and Kkana = 2.5 (±0.6) × 103 M-1 with the order of Cip > Kana. Results of UV-vis were consistent with fluorescence measurements and demonstrated a stronger complexation for Cip rather than Kana. The secondary structure of ß-LG was preserved upon interaction with Kana; however, a reduction in ß-sheet content from 39.1 to 31.9% was convoyed with an increase in α-helix from 12.8 to 20.5% due to complexation of Cip. Molecular docking studies demonstrated that preferred binding sites of these drugs are not the same and several amino acids are involved in stabilizing the interaction. Based on the achieved results, Kana and Cip can spontaneously bind to ß-LG and this protein may serve as their transport vehicle.
Asunto(s)
Ciprofloxacina/química , Sistemas de Liberación de Medicamentos , Kanamicina/química , Lactoglobulinas/química , Sitios de Unión/efectos de los fármacos , Ciprofloxacina/uso terapéutico , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Kanamicina/uso terapéutico , Lactoglobulinas/uso terapéutico , Simulación del Acoplamiento Molecular , Unión Proteica/efectos de los fármacosRESUMEN
Bovine milk ß-lactoglobulin (ß-LG) demonstrates significant resistance against both gastric- and simulated duodenal digestions. Therefore, it seems a realistic protein candidate for safe delivery and protection of particularly pH sensitive drugs in stomach. Recently, pyrimidine fused heterocycles (PFHs) revealed inhibitory properties against α-glucosidase (α-Gls) which is an important target enzyme for those drugs playing significant role in treatment of type-II diabetes and HIV/AIDS infection. The delivery of these compounds to small intestine where the enzyme plays its biological function is of great importance. Therefore, in this work the interaction of PFH compounds with ß-LG, as a carrier protein has been investigated. Fluorescence, circular dichroism (CD) and UV-vis spectroscopic studies were used to examine the binding parameters and binding modes of the interaction. Moreover, the effects of PFH complexation on the secondary structures of ß-LG were studied. All of these compounds significantly quenched the fluorescence intensity of ß-LG due to a ground state complex formation. The binding and thermodynamic parameters were calculated. While hydrophobic interactions were proved to play significant role in the interaction of L1, L2 and L3, hydrogen bonding was shown to be important in the complexation of L4. The secondary structures of ß-LG were preserved upon interaction of these synthetic compounds. Based on the achieved results, these potentially therapeutic agents can significantly bind to ß-LG. Consequently, this protein might be useful for delivery of PFH compounds to small intestine where representing their potential ability to inhibit α-Gls and to reduce the postprandial hyperglycemia in diabetic patients.
Asunto(s)
Portadores de Fármacos/química , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Compuestos Heterocíclicos con 3 Anillos/química , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/química , Lactoglobulinas/química , Pirimidinonas/administración & dosificación , Pirimidinonas/química , Animales , Proteínas Portadoras/química , Bovinos , Dicroismo Circular , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Sistemas de Liberación de Medicamentos , Diseño de Fármacos , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Inhibidores de Glicósido Hidrolasas , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Humanos , Hiperglucemia/prevención & control , Hipoglucemiantes/farmacocinética , Intestino Delgado/efectos de los fármacos , Intestino Delgado/metabolismo , Ligandos , Unión Proteica , Estructura Secundaria de Proteína , Pirimidinas/química , Pirimidinonas/farmacocinética , Espectrometría de Fluorescencia , Espectrofotometría , TermodinámicaRESUMEN
The synthesis of a set of pyrimidine-fused derivatives (L1-L8), resulting from the incorporation of different fragments on the pyrimidine-fused heterocycle (PFH) of the earlier reported α-glucosidase (α-Gls) inhibitor (C1-C5), allowed the discovery of new ligands with modest and selective inhibitory activity. The PFH core (substructure 2) was proved to play a significant role in their inhibitory properties. Additionally, the substituent on substructures 1 and 3 of the heterocyclic ring was demonstrated to be important in the enzyme inhibitory action of the pyrimidine-fused derivatives. Moreover, these ligands show selective inhibitory properties for α-Gls over porcine pancreatic α-amylase (α-Amy) which is important in terms of their reduced susceptibility for the possible development of intestinal disturbance side effects. Therefore, low to moderate α-Amy inhibition with effective α-Gls inhibitory action may offer a better therapeutic strategy. Overall, these compounds can potentially offer a new opportunity to develop novel antidiabetic drugs with selective inhibitory action against α-Gls.