Due to the shallow and hydrophilic binding sites of carbohydrate-binding proteins, the design of glycomimetics is often complicated by high desolvation costs as well as competition with solvent. Therefore, a careful optimization of interaction vectors and ligand properties is required in the design and optimization of glycomimetics. Here, we employ thermodynamics-guided design to optimize mannose-based glycomimetics targeting the human C-type lectin receptor dendritic cell-specific intercellular adhesion molecule 3 grabbing nonintegrin (DC-SIGN), a pathogenic host factor in viral infections.
View Article and Find Full Text PDFThe selectin family consisting of E-, P- and L-selectin plays dominant roles in atherosclerosis, ischemia-reperfusion injury, inflammatory diseases, and metastatic spreading of some cancers. An early goal in selectin-targeted drug discovery campaigns was to identify ligands binding to all three selectins, so-called pan-selectin antagonists. The physiological epitope, tetrasaccharide sialyl Lewis (sLe, 1) binds to all selectins, albeit with very different affinities.
View Article and Find Full Text PDFThe pharmacological modulation of disease-relevant carbohydrate-protein interactions represents an underexplored area of medicinal chemistry. One particular challenge in the design of glycomimetic compounds is the inherent instability of the glycosidic bond toward enzymatic cleavage. This problem has traditionally been approached by employing S-, N-, or C-glycosides with reduced susceptibility toward glycosidases.
View Article and Find Full Text PDFArch Pharm (Weinheim)
April 2024
Many viruses exploit the human C-type lectin receptor dendritic cell-specific ICAM-3 grabbing nonintegrin (DC-SIGN) for cell entry and virus dissemination. An inhibition of DC-SIGN-mediated virus attachment by glycan-derived ligands has, thus, emerged as a promising strategy toward broad-spectrum antiviral therapeutics. In this contribution, several cognate fragments of oligomannose- and complex-type glycans grafted onto a poly-l-lysine scaffold are evaluated as polyvalent DC-SIGN ligands.
View Article and Find Full Text PDFSiglec-7 regulates immune cell activity and is a promising target for immunomodulation. Here, we report the discovery of novel sialic acid derivatives binding to Siglec-7. Synthesis and affinity measurements are complemented by high-quality models of sialoside-Siglec-7 complexes based on molecular dynamics (MD) simulations on the microsecond time scale.
View Article and Find Full Text PDFBackground And Aims: For patients with congenitally corrected transposition of the great arteries (ccTGA), factors associated with progression to end-stage congestive heart failure (CHF) remain largely unclear.
Methods: This multicentre, retrospective cohort study included adults with ccTGA seen at a congenital heart disease centre. Clinical data from initial and most recent visits were obtained.
Mammarenaviruses are enveloped RNA viruses that can be associated with rodent-transmitted diseases in humans. Their virions are composed of a nucleocapsid surrounded by a lipid bilayer with glycoprotein (GP) spikes interacting with receptors on target cells. Both the GP and receptors are highly glycosylated, with glycosylation patterns being crucial for virus binding and cell entry, viral tropism, immune responses, or therapy strategies.
View Article and Find Full Text PDFBackground: For patients with d-loop transposition of the great arteries (d-TGA) with a systemic right ventricle after an atrial switch operation, there is a need to identify risks for end-stage heart failure outcomes.
Objectives: The authors aimed to determine factors associated with survival in a large cohort of such individuals.
Methods: This multicenter, retrospective cohort study included adults with d-TGA and prior atrial switch surgery seen at a congenital heart center.
Antibiotic resistance is a major worldwide concern, and new drugs with mechanistically novel modes of action are urgently needed. Here, we report the structure-based drug design, synthesis, and evaluation in vitro and in cellular systems of sialic acid derivatives able to inhibit the bacterial sialic acid symporter SiaT. We designed and synthesized 21 sialic acid derivatives and screened their affinity for SiaT by a thermal shift assay and elucidated the inhibitory mechanism through binding thermodynamics, computational methods, and inhibitory kinetic studies.
View Article and Find Full Text PDFGuidelines for the diagnosis and treatment of hypertension were published by the American Heart Association (AHA) in 2017. The prevalence of hypertension in adults with congenital heart disease (ACHD) under these guidelines has yet to be characterized. We sought to assess the prevalence, impact, and provider response to hypertension under current guidelines.
View Article and Find Full Text PDFRSC Med Chem
December 2021
In their role as pattern-recognition receptors on cells of the innate immune system, myeloid C-type lectin receptors (CLRs) assume important biological functions related to immunity, homeostasis, and cancer. As such, this family of receptors represents an appealing target for therapeutic interventions for modulating the outcome of many pathological processes, in particular related to infectious diseases. This review summarizes the current state of research into glycomimetic or drug-like small molecule ligands for the CLRs Mincle, Langerin, and DC-SIGN, which have potential therapeutic applications in vaccine research and anti-infective therapy.
View Article and Find Full Text PDFInt J Cardiol Congenit Heart Dis
March 2022
Background: The 2011 American Heart Association best practices statement on transition for young adults with congenital heart disease (CHD) addresses both medical transfer of care and transition to independent adulthood. The statement specifically includes information regarding both medical and lifestyle issues. The aim of this study is to evaluate medical and lifestyle-related areas of knowledge of teens with CHD to help identify targets for potential intervention.
View Article and Find Full Text PDFThe C-type lectin receptor DC-SIGN is a pattern recognition receptor expressed on macrophages and dendritic cells. It has been identified as a promiscuous entry receptor for many pathogens, including epidemic and pandemic viruses such as SARS-CoV-2, Ebola virus, and HIV-1. In the context of the recent SARS-CoV-2 pandemic, DC-SIGN-mediated virus dissemination and stimulation of innate immune responses has been implicated as a potential factor in the development of severe COVID-19.
View Article and Find Full Text PDFIn biological systems, polar interactions are heavily burdened by high desolvation penalties resulting from strong solute-solvent interactions. As a consequence thereof, enthalpic contributions of hydrogen bonds to the free energy of binding are severely diminished. However, this effect is strongly attenuated for interactions within solvent-shielded areas of proteins.
View Article and Find Full Text PDFThe C-type lectin receptor DC-SIGN mediates interactions with envelope glycoproteins of many viruses such as SARS-CoV-2, ebola, and HIV and contributes to virus internalization and dissemination. In the context of the recent SARS-CoV-2 pandemic, involvement of DC-SIGN has been linked to severe cases of COVID-19. Inhibition of the interaction between DC-SIGN and viral glycoproteins has the potential to generate broad spectrum antiviral agents.
View Article and Find Full Text PDFBackground: Adults with congenital heart disease (CHD) have been considered potentially high risk for novel coronavirus disease-19 (COVID-19) mortality or other complications.
Objectives: This study sought to define the impact of COVID-19 in adults with CHD and to identify risk factors associated with adverse outcomes.
Methods: Adults (age 18 years or older) with CHD and with confirmed or clinically suspected COVID-19 were included from CHD centers worldwide.
Burkholderia cenocepacia is an opportunistic Gram-negative bacterium that causes infections in patients suffering from chronic granulomatous diseases and cystic fibrosis. It displays significant morbidity and mortality due to extreme resistance to almost all clinically useful antibiotics. The bacterial lectin BC2L-C expressed in B.
View Article and Find Full Text PDFBackground: Amongst patients with CHD, the time of transition to adulthood is associated with lapses in care leading to significant morbidity. The purpose of this study was to identify differences in perceptions between parents and teens in regard to transition readiness.
Methods: Responses were collected from 175 teen-parent pairs via the validated CHD Transition Readiness survey and an information request checklist.
Background: This study evaluated hepatic stiffness by shear wave elastography to investigate subclinical hepatic changes in a cohort of patients with congenital biventricular heart disease (BHD).
Methods: The BHD patients and age-matched healthy controls were prospectively recruited for hepatic ultrasonography and shear wave elastography. Real-time B-mode imaging with Doppler was performed for celiac axis, superior mesenteric artery, and main portal vein, and hepatic shear wave elastography was assessed.
Objectives: To examine changes in transition readiness (knowledge, self-efficacy, self-management) over time and explore factors associated with transition readiness, including psychosocial quality of life (QOL) and health service utilization in teens/young adults with congenital heart disease.
Study Design: In a multicenter prospective cohort study, 356 patients, age 14-27 years, completed transition readiness and QOL assessments at routine cardiology visits at baseline and 1-year follow-up.
Results: Median patient age was 19.