RESUMO
CHEMICAL ENHANCEMENT: Designed to target HIV-1 protease, a novel γ-hydroxyphosphonate has been found to significantly enhance viral replication in a panel of clinically relevant R5 HIV-1 isolates. This unexpected result constitutes the first instance of a small molecule capable of doing this, and it has implications for the preparation and use of R5 isolates in vaccine and drug development.
Assuntos
Inibidores da Protease de HIV/química , Inibidores da Protease de HIV/farmacologia , Protease de HIV/metabolismo , HIV-1/efeitos dos fármacos , HIV-1/crescimento & desenvolvimento , Bibliotecas de Moléculas Pequenas/farmacologia , Replicação Viral/efeitos dos fármacos , Relação Dose-Resposta a Droga , Inibidores da Protease de HIV/síntese química , HIV-1/isolamento & purificação , Testes de Sensibilidade Microbiana , Estrutura Molecular , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-AtividadeRESUMO
Literature publications reporting the development of organophosphorus compounds, targeting aspects of signal transduction to the titled therapeutic ends, are reviewed. With respect to extracellular targets, the development of ligands to purinergic (P2), and endothelial differentiation-gene receptors (of S1P- and LPA-receptor subtypes) is charted, along with inhibitors of the production and release of tumour necrosis factor-alpha (TNF-alpha). Reported also are inhibitors of the ectoenzymes aminopeptidase N, aminopeptidase A and dipeptidyl peptidase IV, the proteolytic enzyme thrombin, ligands to "apoptosis-receptors" and gammadelta T-cell activators. In addition, disruption of intracellular signalling chains mediated through reversible coupling of proteins via phosphorylation of Tyr residues and docking of pTyr residues in SH2-binding domains is covered. In particular, the development of ligands to SH2-binding domains in tyrosine kinases Src and lck, adaptor protein Grb2, and also ZAP70 protein are reported along with inhibitors to relevant phosphatases. SAR studies of ligands to Ins(1,4,5)-P3- and ryanodine-type receptors of intracellular Ca2+-storage organelles are described including analogues to secondary messengers cyclic-ADP-ribose (cADPR) and myo-inositol-1,4,5-triphosphate. Inhibitors of phosphatidyl inositol 3-kinase (PI3K) and sphingomyelinase are also reported, as are inhibitors of farnesyl transferase, the enzyme involved in protein-prenylation.
