RESUMO
Glycosaminoglycan (GAG) sequences that selectively target heparin cofactor II (HCII), a key serpin present in human plasma, remain unknown. Using a computational strategy on a library of 46 656 heparan sulfate hexasaccharides we identified a rare sequence consisting of consecutive glucuronic acid 2-O-sulfate residues as selectively targeting HCII. This and four other unique hexasaccharides were chemically synthesized. The designed sequence was found to activate HCII ca. 250-fold, while leaving aside antithrombin, a closely related serpin, essentially unactivated. This group of rare designed hexasaccharides will help understand HCII function. More importantly, our results show for the first time that rigorous use of computational techniques can lead to discovery of unique GAG sequences that can selectively target GAG-binding protein(s), which may lead to chemical biology or drug discovery tools.
Assuntos
Glucuronatos/farmacologia , Cofator II da Heparina/agonistas , Heparitina Sulfato/farmacologia , Descoberta de Drogas , Glucuronatos/química , Cofator II da Heparina/metabolismo , Heparitina Sulfato/química , Humanos , Ligação Proteica , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologiaRESUMO
Glutaric Aciduria type 1 (GA 1) is an inherited disorder of lysine and tryptophan catabolism that typically manifests in infants with acute cerebral injury associated with intercurrent illness. We investigated the clinical, biochemical and molecular features in 14 known GA 1 patients in South Africa, most of whom were recently confirmed following the implementation of sensitive urine organic acid screening at our laboratory. Age at diagnosis ranged from 3days to 5years and poor clinical outcome reflected the delay in diagnosis in all but one patient. Twelve patients were unrelated black South Africans of whom all those tested (n=11) were found homozygous for the same A293T mutation in the glutaryl-CoA dehydrogenase (GCDH) gene. Excretion of 3-hydroxyglutarate (3-OHGA) was >30.1µmol/mmol creatinine (reference range <2.5) in all cases but glutarate excretion varied with 5 patients considered low excretors (glutarate <50µmol/mmol creatinine). Fibroblast GCDH activity was very low or absent in all of five cases tested. Heterozygosity for the A293T mutation was found 1 in 36 (95% CI; 1/54 - 1/24) unrelated black South African newborns (n=750) giving a predicted prevalence rate for GA 1 of 1 in 5184 (95% CI; 1/11664 - 1/2304) in this population. GA 1 is a treatable but often missed inherited disorder with a previously unrecognised high carrier frequency of a single mutation in the South African black population.
Assuntos
Glutaril-CoA Desidrogenase/deficiência , Erros Inatos do Metabolismo dos Aminoácidos/epidemiologia , Erros Inatos do Metabolismo dos Aminoácidos/genética , População Negra/genética , Encefalopatias Metabólicas/epidemiologia , Encefalopatias Metabólicas/genética , Pré-Escolar , Feminino , Glutaril-CoA Desidrogenase/genética , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , África do Sul/epidemiologiaAssuntos
Antimaláricos/farmacologia , Cloroquina/química , Hemeproteínas/antagonistas & inibidores , Pirimidinas/síntese química , Pirimidinas/metabolismo , Animais , Química Farmacêutica/métodos , Cloroquina/farmacologia , Desenho de Fármacos , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Modelos Biológicos , Modelos Químicos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Reaction of the bis-alkenyl complex cis-[Pt(PPh3)2(CH2CH2CH=CH2)2] with Grubbs 1st generation catalyst gives, in high yield, the metallacycloalkene cis-[Pt(PPh3)2(CH2CH2CH=CHCH2CH2)], which can be hydrogenated to the metallacycloalkane cis-[Pt(PPh3)2(CH2)6].
