Novel Chemotypes for Inhibition of Bacterial and Mammalian Carbohydrate-Binding Proteins

The carbohydrate-binding proteins (lectins) emerged as viable targets to combat viral as well as bacterial pathogens. Therefore, drugs targeting lectins are desired; however their identification and development is challenging and is currently primarily focused on carbohydrate−based inhibitors. Therefore, new strategies and sensitive methods are required. Fragment-based drug design (FBDD) has proven to be a promising strategy for approaching difficult targets such as lectins. To address the current limitations in design of drug-like inhibitors for lectins, non- and metal-dependent bacterial or mammalian lectins are used. First, bacterial lectins from the opportunistic human pathogens Pseudomonas aeruginosa (LecA (PA-IL) and LecB (PA-IIL)) and Burkholderia ambifaria (BambL) were employed as models to establish ligand- (F- glycan) and protein-observed 19F NMR (PrOF) methods for drug discovery. To demonstrate the utility of these methods for fragment-based drug discovery (FBDD), a druggable pocket in BambL was uncovered as a potential target site for allosteric inhibitors. Finally, these methods were employed as well as other biophysical (X-ray, SPR), computational and biochemical techniques to discover a novel class of drug-like molecules for targeting the carbohydrate-binding site of metal-dependent bacterial and mammalian lectins. Together, the 19F NMR-based methods and discovery of metal- binding pharmacophores (MBPs) as novel chemotypes will support the development of small molecule inhibitors for metal-dependent lectins and bacterial lectins as new therapeutic approaches against antibiotic-resistant pathogens

How glycobiology can help us treat and beat the COVID-19 pandemic

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged during the last months of 2019, spreading throughout the world as a highly transmissible infectious illness designated as COVID-19. Vaccines have now appeared, but the challenges in producing sufficient material and distributing them around the world means that effective treatments to limit infection and improve recovery are still urgently needed. This review focuses on the relevance of different glycobiological molecules that could potentially serve as or inspire therapeutic tools during SARS-CoV-2 infection. As such, we highlight the glycobiology of the SARS-CoV-2 infection process, where glycans on viral proteins and on host glycosaminoglycans have critical roles in efficient infection. We also take notice of the glycan-binding proteins involved in the infective capacity of virus and in human defense. In addition, we critically evaluate the glycobiological contribution of candidate drugs for COVID-19 therapy such as glycans for vaccines, anti-glycan antibodies, recombinant lectins, lectin inhibitors, glycosidase inhibitors, polysaccharides, and numerous glycosides, emphasizing some opportunities to repurpose FDA-approved drugs. For the next-generation drugs suggested here, biotechnological engineering of new probes to block the SARS-CoV-2 infection might be based on the essential glycobiological insight on glycosyltransferases, glycans, glycan-binding proteins, and glycosidases related to this pathology.publishedVersionFil: Lardone, Ricardo Dante. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas; Argentina.Fil: Lardone, Ricardo Dante. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentina.Fil: Garay, Yohana Camila. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas; Argentina.Fil: Garay, Yohana Camila. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentina.Fil: Parodi, Pedro. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas; Argentina.Fil: Parodi, Pedro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentina.Fil: de la Fuente, Sofia. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas; Argentina.Fil: de la Fuente, Sofia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentina.Fil: Angeloni, Genaro. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas; Argentina.Fil: Angeloni, Genaro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentina.Fil: Bravo, Eduardo O. Gobierno de la Provincia de Buenos Aires. Hospital Interzonal de Agudos San Roque de Gonnet; ArgentinaFil: Schmider, Anneke K. Psychiatrische Klinik Lüneburg; AlemaniaFil: Irazoqui, Fernando José. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas; Argentina.Fil: Irazoqui, Fernando José. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentina

Dengue virus entry and trafficking: Perspectives as antiviral target for prevention and therapy

Dengue virus (DENV) is the etiological agent of the most important human viral infection transmitted by mosquitoes in the world. In spite of the serious health threat that dengue represents, at present there are no vaccine or antiviral agents available and treatment of patients consists of supportive therapy. This review will focus on the process of DENV entry into the host cell as a potential target for antiviral therapy. The recent advances in the knowledge of viral and cellular molecules and mechanisms involved in binding, internalization and trafficking of DENV into the host cell until virion uncoating are discussed, together with an overview of the strategies and compounds evaluated for development of antiviral agents targeted to DENV entry.Fil: Castilla, Viviana. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; ArgentinaFil: Piccini, Luana Érica. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Damonte, Elsa Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentin

Los receptores para el reconocimiento de patrones moleculares: aportaciones de la química computacional para el diseño de fármacos y la modulación de la inmunidad innata

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Farmacia, Departamento de Química Orgánica y Farmacéutica, leída el 18/11/2019In this Thesis we have aimed the study of the molecular recognition processes of receptors involved in the innate immunity. More concretely, we have focused in two different types of lectins, Galectins and DC-SIGN, and in Toll-like receptor 4. We have made use of computational techniques, including docking and virtual screening, molecular dynamics simulations, conformational analysis and quantum mechanics calculations. The work has been organized into several chapters that are summarized as follows: Chapter 1 corresponds to the current knowledge and perspectives about receptors related to immunity, in particular: galectins, DC-SIGN, and Toll-like receptor 4, corresponding to the molecular recognition events and modulation by small molecules. Chapter 2 describes the state-of-the-art methods in molecular modeling and computational chemistry applied to the study of molecular recognition processes and drug design...En esta tesis hemos estudiado los procesos reconocimiento molecular de receptores involucrados en la inmunidad innata. Más concretamente, nos hemos centrado en dos tipos diferentes de lectinas, Galectinas y DC-SIGN, y en el receptor Toll-like 4 (TLR4). Hemos utilizado técnicas computacionales, incluyendo docking y cribado virtual, simulaciones de dinámica molecular, análisis conformacional y cálculos de mecánica cuántica. El trabajo se ha organizado en diferentes capítulos que se resumen como sigue: El capítulo 1 corresponde al estado del arte y las perspectivas relacionadas con los estudios de reconocimiento molecular proteína-carbohidrato y diseño de nuevos moduladores con actividad biológica en receptores de la inmunidad, en particular galectinas, DC-SIGN y el receptor Toll-like 4. El capítulo 2 describe el estado actual de los métodos en modelado molecular y química computacional aplicados al estudio de los procesos de reconocimiento molecular y diseño de fármacos...Fac. de FarmaciaTRUEunpu

An Indian effort towards affordable drugs: "generic to designer drugs"

This review discusses the progress of India from being one of the largest producers of generics to its coming of age and initiating novel drug development programs such as the Open Source Drug Discovery for tuberculosis. A few groups have also begun to emerge which focus their research on rational or structure based drug design. We discuss here some of the ongoing efforts in drug discovery in India primarily in national research institutions and academia