Sickle cell disease is a very variable condition, with outcomes ranging from death in childhood to living relatively symptom free into the 8th decade. Much of this variability is unexplained. The ...co-inheritance of α thalassaemia and factors determining HbF levels significantly modify the phenotype, but few other significant genetic variants have been identified, despite extensive studies. Environmental factors are undoubtedly important, with socio-economics and access to basic medical care explaining the huge differences in outcomes between many low- and high-income countries. Exposure to cold and windy weather seems to precipitate acute complications in many people, although these effects are unpredictable and vary with geography. Many studies have tried to identify prognostic factors which can be used to predict outcomes, particularly when applied in infancy. Overall, low haemoglobin, low haemoglobin F percentage and high reticulocytes in childhood are associated with worse outcomes, although again these effects are fairly weak and inconsistent.
The popularity of fragment-based drug discovery (FBDD) is demonstrated by the number of recent successful fragment-to-lead (F2L) publications. This Miniperspective provides a tabulated summary of the ...F2L literature published in the year 2016, along with discussion of general trends. It uses the same format as our summary of the 2015 literature and is intended to be a resource for both FBDD practitioners and medicinal chemists in general.
Fragment-based drug discovery (FBDD) is now well-established as a technology for generating new chemical leads and drugs. This Miniperspective provides a tabulated overview of the fragment-to-lead ...literature published in the year 2015, together with a commentary on trends observed across the FBDD field during this time. It is hoped that this tabulated summary will provide a useful point of reference for both FBDD practitioners and the wider medicinal chemistry community.
We have analysed 131 fragment-to-lead (F2L) examples targeting a wide variety of protein families published by academic and industrial laboratories between 2015-2019. Our assessment of X-ray ...structural data identifies the most common polar functional groups involved in fragment-protein binding are: N-H (hydrogen bond donors on aromatic and aliphatic N-H, amides and anilines; totalling 35%), aromatic nitrogen atoms (hydrogen bond acceptors; totalling 23%), and carbonyl oxygen group atoms (hydrogen bond acceptors on amides, ureas and ketones; totalling 22%). Furthermore, the elaboration of each fragment into its corresponding lead is analysed to identify the nominal synthetic growth vectors. In ∼80% of cases, growth originates from an aromatic or aliphatic carbon on the fragment and more than 50% of the total bonds formed are carbon-carbon bonds. This analysis reveals that growth from carbocentric vectors is key and therefore robust C-H functionalisation methods that tolerate the innate polar functionality on fragments could transform fragment-based drug discovery (FBDD). As a further resource to the community, we have provided the full data of our analysis as well as an online overlay page of the X-ray structures of the fragment hit and leads:
https://astx.com/interactive/F2L-2021/
An in depth meta analysis of 131 fragment-to-lead case-studies has shown the importance of synthetic methods that allow carbon-centred synthetic elaboration in the presence of polar pharmacophores.
Introduction: Therapeutic options for sickle cell disease (SCD) are limited and, currently, only one drug (hydroxyurea) has FDA approval for the treatment of adult SCD. While this genetic disease is ...caused by hemoglobin polymerization, subsequent downstream events trigger platelet activation, vaso-occlusion and the disease's complex pathophysiology.
Areas covered: The oral thienopyridine, prasugrel hydrochloride, irreversibly inhibits the P2Y12 receptors, inhibiting ADP-dependent platelet activation. We discuss recent clinical trials evaluating the pharmokinetics of prasugrel and its potential for use in SCD.
Expert opinion: Prasugrel administration in SCD appears to be well tolerated and safe. However, although this drug modestly inhibits platelet activity in these patients, administration of prasugrel to a large group of children and adolescents for up to 24 months failed to convincingly reduce vaso-occlusive complications. Speculatively, prasugrel may be of occasional use for off-license purposes in patients unable or unwilling to take hydroxyurea (particularly in 12-17-year olds). Although there is currently no prospect of prasugrel being licensed for use in SCD, the success of on-going trials of other antiplatelet agents in SCD might lead to further trials of prasugrel in SCD.
The porphyrias are a group of rare, mainly inherited, diseases caused by a deficiency of one of the enzymes of the haem biosynthesis pathway. The biochemical hallmark of an acute attack is an ...increase in urine porphobilinogen (PBG), together with an increase in urinary excretion of δ-aminolaevulinic acid (ALA) and total urine porphyrins (TUP). In patients with acute intermittent porphyria (AIP) the concentrations of the porphyrin precursors are thought to remain elevated for many years following an acute attack, although this has not been well documented.
We measured urine ALA, PBG and TUP excretion in 20 patients with AIP following an attack of acute porphyria over a time period of 3 months to 23 years after their last documented acute attack.
We showed that urinary concentrations of all metabolites remain elevated for many years. The urinary half life of TUP was 5.3 years, ALA 7.7 years and PBG 10.6 years. Even after 20 years, PBG concentrations remained elevated above the normal range.
Our study highlights the difficulties of using urinary analysis for diagnosing recurrent attacks, and also raises important questions about the pathophysiology of the condition.
In both sickle cell disease and malaria, red blood cells (RBCs) are phagocytosed in the spleen, but receptor-ligand pairs mediating uptake have not been identified. Here, we report that patches of ...high mannose N-glycans (Man
GlcNAc
), expressed on diseased or oxidized RBC surfaces, bind the mannose receptor (CD206) on phagocytes to mediate clearance. We find that extravascular hemolysis in sickle cell disease correlates with high mannose glycan levels on RBCs. Furthermore, Plasmodium falciparum-infected RBCs expose surface mannose N-glycans, which occur at significantly higher levels on infected RBCs from sickle cell trait subjects compared to those lacking hemoglobin S. The glycans are associated with high molecular weight complexes and protease-resistant, lower molecular weight fragments containing spectrin. Recognition of surface N-linked high mannose glycans as a response to cellular stress is a molecular mechanism common to both the pathogenesis of sickle cell disease and resistance to severe malaria in sickle cell trait.
Summary
Phosphatidylserine (PS) exposure increases as red cells age, and is an important signal for the removal of senescent cells from the circulation. PS exposure is elevated in red cells from ...sickle cell anaemia (SCA) patients and is thought to enhance haemolysis and vaso‐occlusion. Although precise conditions leading to its externalisation are unclear, high intracellular Ca2+ has been implicated. Red cells from SCA patients are also exposed to an increased oxidative challenge, and we postulated that this stimulates PS exposure, through increased Ca2+ levels. We tested four different ways of generating oxidative stress: hypoxanthine and xanthine oxidase, phenazine methosulphate, nitrite and tert‐butyl hydroperoxide, together with thiol modification with N‐ethylmaleimide (NEM), dithiothreitol and hypochlorous acid (HOCl), in red cells permeabilised to Ca2+ using bromo‐A23187. Unexpectedly, our findings showed that the four oxidants significantly reduced Ca2+‐induced PS exposure (by 40–60%) with no appreciable effect on Ca2+ affinity. By contrast, NEM markedly increased PS exposure (by about 400%) and slightly but significantly increased the affinity for Ca2+. Dithiothreitol modestly reduced PS exposure (by 25%) and HOCl had no effect. These findings emphasise the importance of thiol modification for PS exposure in sickle cells but suggest that increased oxidant stress alone is not important.
Malaria parasites such as Plasmodium falciparum have exerted formidable selective pressures on the human genome. Of the human genetic variants associated with malaria protection, beta thalassaemia (a ...haemoglobinopathy) was the earliest to be associated with malaria prevalence. However, the malaria protective properties of beta thalassaemic erythrocytes remain unclear. Here we studied the mechanics and surface protein expression of beta thalassaemia heterozygous erythrocytes, measured their susceptibility to P. falciparum invasion, and calculated the energy required for merozoites to invade them. We found invasion-relevant differences in beta thalassaemic cells versus matched controls, specifically: elevated membrane tension, reduced bending modulus, and higher levels of expression of the major invasion receptor basigin. However, these differences acted in opposition to each other with respect to their likely impact on invasion, and overall we did not observe beta thalassaemic cells to have lower P. falciparum invasion efficiency for any of the strains tested.
PDF
