ABSTRACT
INTRODUCTION: Supplementary immunization activities (SIAs) aim to interrupt measles transmission by reaching susceptible children, including children who have not received the recommended two routine doses of MCV before the SIA. However, both strategies may miss the same children if vaccine doses are highly correlated. How well SIAs reach children missed by routine immunization is a key metric in assessing the added value of SIAs. METHODS: Children aged 9 months to younger than 5 years were enrolled in cross-sectional household serosurveys conducted in five districts in India following the 2017-2019 measles-rubella (MR) SIA. History of measles containing vaccine (MCV) through routine services or SIA was obtained from documents and verbal recall. Receipt of a first or second MCV dose during the SIA was categorized as "added value" of the SIA in reaching un- and under-vaccinated children. RESULTS: A total of 1,675 children were enrolled in these post-SIA surveys. The percentage of children receiving a 1st or 2nd dose through the SIA ranged from 12.8% in Thiruvananthapuram District to 48.6% in Dibrugarh District. Although the number of zero-dose children prior to the SIA was small in most sites, the proportion reached by the SIA ranged from 45.8% in Thiruvananthapuram District to 94.9% in Dibrugarh District. Fewer than 7% of children remained measles zero-dose after the MR SIA (range: 1.1-6.4%) compared to up to 28% before the SIA (range: 7.3-28.1%). DISCUSSION: We demonstrated the MR SIA provided considerable added value in terms of measles vaccination coverage, although there was variability across districts due to differences in routine and SIA coverage, and which children were reached by the SIA. Metrics evaluating the added value of an SIA can help to inform the design of vaccination strategies to better reach zero-dose or undervaccinated children.
Subject(s)
Measles , Rubella , Humans , Child , Infant , Cross-Sectional Studies , Immunization Programs , Measles/prevention & control , Rubella/prevention & control , Vaccination , Measles Vaccine , ImmunizationABSTRACT
Clinically used BCR-ABL1 inhibitors for the treatment of chronic myeloid leukemia do not eliminate leukemic stem cells (LSC). It has been shown that MNK1 and 2 inhibitors prevent phosphorylation of eIF4E and eliminate the self-renewal capacity of LSCs. Herein, we describe the identification of novel dual MNK1 and 2 and BCR-ABL1 inhibitors, starting from the known kinase inhibitor 2. Initial structure-activity relationship studies resulted in compound 27 with loss of BCR-ABL1 inhibition. Further modification led to orally bioavailable dual MNK1 and 2 and BCR-ABL1 inhibitors 53 and 54, which are efficacious in a mouse xenograft model and also reduce the level of phosphorylated eukaryotic translation initiation factor 4E in the tumor tissues. Kinase selectivity of these compounds is also presented.
Subject(s)
Fusion Proteins, bcr-abl/antagonists & inhibitors , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Administration, Oral , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Biological Availability , Chemistry Techniques, Synthetic , Dose-Response Relationship, Drug , Eukaryotic Initiation Factor-4E/metabolism , Female , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Mice, SCID , Molecular Targeted Therapy/methods , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemistry , Structure-Activity Relationship , Xenograft Model Antitumor Assays/methodsABSTRACT
Porcupine is a component of the Wnt pathway which regulates cell proliferation, migration, stem cell self-renewal, and differentiation. The Wnt pathway has been shown to be dysregulated in a variety of cancers. Porcupine is a membrane bound O-acyltransferase that palmitoylates Wnt. Inhibiting porcupine blocks the secretion of Wnt and effectively inhibits the Wnt pathway. Using high throughput screening, we have identified a number of novel porcupine inhibitors with diverse scaffolds. The pharmacophore requirements for our porcupine inhibitors were elucidated, and a pharmacophore model is proposed. Our compounds as well as all currently published porcupine inhibitors may be fitted to this model in low energy conformations with good superimposition of the pharmacophore elements. The model also explains the stereochemical requirements of our chiral porcupine inhibitors. The pharmacophore model was successfully used for designing 3 new series of porcupine inhibitors having a tricyclic xantine, a phtalimide, or a piperidine-maleimide scaffold.
Subject(s)
Drug Design , Membrane Proteins/antagonists & inhibitors , Models, Molecular , Wnt Proteins/antagonists & inhibitors , Acyltransferases , HEK293 Cells , Humans , Molecular Conformation , Stereoisomerism , Substrate SpecificityABSTRACT
A novel class of compounds containing N-sulfonylanthranilic acid was found to specifically inhibit dengue viral polymerase. The structural requirements for inhibition and a preliminary structure-activity relationship are described. A UV cross-linking experiment was used to map the allosteric binding site of the compound on the viral polymerase.
Subject(s)
Dengue Virus/enzymology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , RNA-Dependent RNA Polymerase/antagonists & inhibitors , ortho-Aminobenzoates/chemistry , ortho-Aminobenzoates/pharmacology , Binding Sites , Dengue Virus/chemistry , Dengue Virus/drug effects , Enzyme Inhibitors/chemical synthesis , Humans , Inhibitory Concentration 50 , Models, Molecular , RNA-Dependent RNA Polymerase/chemistry , Structure-Activity Relationship , Sulfinic Acids/chemical synthesis , Sulfinic Acids/chemistry , Sulfinic Acids/pharmacology , ortho-Aminobenzoates/chemical synthesisABSTRACT
Substrate-based tetrapeptide inhibitors with various warheads were designed, synthesized, and evaluated against the Dengue virus NS3 protease. Effective inhibition was achieved by peptide inhibitors with electrophilic warheads such as aldehyde, trifluoromethyl ketone, and boronic acid. A boronic acid has the highest affinity, exhibiting a K(i) of 43 nM.
Subject(s)
Chemistry, Pharmaceutical/methods , Dengue Virus/enzymology , Drug Design , Peptides/pharmacology , Protease Inhibitors/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/chemistry , Boronic Acids/chemistry , Dose-Response Relationship, Drug , Enzyme Inhibitors/pharmacology , Ketones/chemistry , Kinetics , Models, Chemical , Peptides/chemistry , Protease Inhibitors/pharmacology , RNA Helicases/antagonists & inhibitors , RNA Helicases/chemistry , Serine Endopeptidases/chemistry , Substrate Specificity , Time FactorsABSTRACT
To identify biologically relevant and drug-like protein ligands for medicinal chemistry and chemical biology research the grouping of proteins according to evolutionary relationships and conservation of molecular recognition is an established method. We propose to employ structure similarity clustering of the ligand-sensing cores of protein domains (PSSC) in conjunction with natural product guided compound library development as a synergistic approach for the identification of biologically prevalidated ligands with high fidelity. This is supported by the concepts that (i) in nature spatial structure is more conserved than amino acid sequence, (ii) the number of fold types characteristic for all protein domains is limited, and (iii) the underlying frameworks of natural product classes with multiple biological activities provide evolutionarily selected starting points in structural space. On the basis of domain core similarity considerations and irrespective of sequence similarity, Cdc25A phosphatase, acetylcholinesterase, and 11beta-hydroxysteroid dehydrogenases type 1 and type 2 were grouped into a similarity cluster. A 147-member compound collection derived from the naturally occurring Cdc25A inhibitor dysidiolide yielded potent and selective inhibitors of the other members of the similarity cluster with a hit rate of 2-3%. Protein structure similarity clustering may provide an experimental opportunity to identify supersites in proteins.
Subject(s)
Biological Factors/chemistry , Protein Conformation , 11-beta-Hydroxysteroid Dehydrogenases/antagonists & inhibitors , Acetylcholinesterase/drug effects , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Models, Molecular , Protein Tyrosine Phosphatase, Non-Receptor Type 1 , cdc25 Phosphatases/antagonists & inhibitorsABSTRACT
Nucleoproteins are naturally occurring biopolymers in which the hydroxy group of a serine, a threonine, or a tyrosine moiety is linked through a phosphodiester group to the 3'- or 5'-end of a nucleic acid. For the study of the biological phenomena in which nucleoproteins are involved, for example, viral replication, nucleopeptides embodying the characteristic linkage between the peptide chain and the oligonucleotide may serve as powerful tools. However, as a result of the multifunctionality and the pronounced acid and base lability of nucleopeptides, their synthesis requires the application of a variety of orthogonally stable blocking groups, which can be removed under the mildest conditions. We have developed a new mild enzymatic deprotection method, that is, the penicillin G acylase-catalyzed hydrolysis of the N-phenylacetoxybenzyloxycarbony (PhAcOZ) group, for the synthesis of nucleopeptides. We demonstrate the wide applicability of this method by coupling the N-terminally deprotected nucleopeptides 31 a-c with PhAcOZ-protected amino acids and subsequent removal of the N-PhAcOZ group from fully protected nucleotetrapeptides 32 a,b with penicillin G acylase. The reaction conditions are very mild (pH 6.8) so that no undesired side reaction such as cleavage of the nucleotide bond or beta-elimination of the nucleotide was observed.
Subject(s)
Peptides/chemical synthesis , Urethane/chemistry , Amino Acids/chemistry , Indicators and Reagents , Magnetic Resonance Spectroscopy , Penicillin Amidase/chemistry , Phenylacetates/chemistryABSTRACT
Access to broadly applicable linker groups that are stable under a variety of reaction conditions and enable the release of target compounds from polymeric supports under the mildest conditions is a major goal in combinatorial chemistry. Here, we summarize the development of enzymatically cleavable linker groups used to prepare a variety of different target molecules on polymeric supports.
Subject(s)
Combinatorial Chemistry Techniques/methods , Enzymes/chemistry , Polymers/chemistry , Protein ConformationABSTRACT
Three cases of cri du chat syndrome with varying ages of presentation are compared and contrasted to highlight the clinical features and evolution of the phenotype with time.
