RESUMEN
Parasitic characteristics, mutations and resistance of influenza A virus make it difficult for current influenza antiviral drugs to maintain long-term effectiveness. Currently, to design non-adamantane compounds targeting the S31N mutant of M2 proton channel is a promising direction for the development of novel anti-influenza drugs. In our previous research, a pinanamine-based antiviral M090 was discovered to target hemagglutinin instead of M2, with its structure being highly similar to reported M2-S31N inhibitors. Herein, a series of pinane oxime derivatives were designed from scratch and evaluated for anti-influenza activity and their cytotoxicity in vitro. Utilizing a combination of structure-activity relationship analysis, electrophysiological assay and molecular docking, the most potent compound 11h, as a M2-S31N blocker, exhibited excellent activity with EC50 value at the low micromolar level against both H3N2 and H1N1. No significant toxicity of 11h was observed. In addition, compound 11h was located tightly in the pore of the drug-binding site with the thiophene moiety facing down toward the C-terminus, and did not adopt a similar position and orientation as the reference inhibitor.
Asunto(s)
Antivirales/farmacología , Monoterpenos Bicíclicos/farmacología , Diseño de Fármacos , Virus de la Influenza A/efectos de los fármacos , Oximas/farmacología , Animales , Antivirales/síntesis química , Antivirales/química , Monoterpenos Bicíclicos/síntesis química , Monoterpenos Bicíclicos/química , Perros , Relación Dosis-Respuesta a Droga , Células HEK293 , Humanos , Células de Riñón Canino Madin Darby/efectos de los fármacos , Células de Riñón Canino Madin Darby/virología , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Oximas/síntesis química , Oximas/química , Relación Estructura-ActividadRESUMEN
Heparin ï¼Hpï¼ is the most widely used anticoagulant drug in the clinicsï¼ with an annual global output of over 10 billion dollars. Hpï¼ a member of the glycosaminoglycans ï¼GAGsï¼ï¼ is prepared from porcine intestinal mucosa via extractionï¼ separationï¼ and purification. Hp is a linear polysaccharide with repeating disaccharide units. Low-molecular-weight heparins ï¼LMWHsï¼ are depolymerized from Hp via chemical or enzymatic degradation. Compared with Hpï¼ LMWHs exhibit less bleeding side effectï¼ milder immunogenicityï¼ and higher bioavailability when injected subcutaneously. In generalï¼ Hpsï¼ including LMWHsï¼ are high complex drugs with large molecular weights ï¼MWsï¼ï¼ inhomogeneous MW distributionsï¼ and structural heterogeneityï¼ including different degrees and locations of sulfonationï¼ and unique residues generated from different production processes. Thusï¼ developing efficient analytical methods to elucidate the structures of Hps and characterize or quantitate their properties is extremely challenging. Unfortunatelyï¼ this problem limits their quality controlï¼ production optimizationï¼ clinical safety monitoringï¼ and new applications. Research has constantly sought to elucidate the complicated structures of Hp drugs. Among the structural analysis and quality control methods of Hp currently availableï¼ chromatographic methods are the most widely studied and used. Howeverï¼ no literature thoroughly summarizes the specific applications of chromatographic methods in the structural analysisï¼ manufacturing processï¼ and quality control of Hp drugs. This paper systematically organizes and describes recent research progresses of the chromatographic methods used to analyze Hp drugsï¼ including the identification and composition of monosaccharidesï¼ disaccharidesï¼ oligosaccharidesï¼ and polysaccharides. The applicationsï¼ innovationsï¼ and limitations of these chromatographic methods are also summarized in this review. The insights obtained in this study will help production and quality control personnelï¼ as well as drug researchersï¼ obtain a deeper understanding of the complex structures of Hp drugs. This paper also provides a comprehensive reference for the structural analysis and quality control of Hpsï¼ proposes ideas for the development of new quality control methodsï¼ and lays a strong foundation for the in-depth structural elucidation of Hp drugs.