RESUMO
Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates plasma low-density lipoprotein cholesterol (LDL-C) levels by promoting hepatic LDL receptor (LDLR) degradation. Therapeutic antibodies that disrupt PCSK9-LDLR binding reduce LDL-C concentrations and cardiovascular disease risk. The epidermal growth factor precursor homology domain A (EGF-A) of the LDLR serves as a primary contact with PCSK9 via a flat interface, presenting a challenge for identifying small molecule PCSK9-LDLR disruptors. We employ an affinity-based screen of 1013in vitro-translated macrocyclic peptides to identify high-affinity PCSK9 ligands that utilize a unique, induced-fit pocket and partially disrupt the PCSK9-LDLR interaction. Structure-based design led to molecules with enhanced function and pharmacokinetic properties (e.g., 13PCSK9i). In mice, 13PCSK9i reduces plasma cholesterol levels and increases hepatic LDLR density in a dose-dependent manner. 13PCSK9i functions by a unique, allosteric mechanism and is the smallest molecule identified to date with in vivo PCSK9-LDLR disruptor function.
Assuntos
Peptídeos/farmacologia , Pró-Proteína Convertase 9/metabolismo , Receptores de LDL/antagonistas & inibidores , Animais , Relação Dose-Resposta a Droga , Células Hep G2 , Humanos , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Peptídeos/síntese química , Peptídeos/química , Conformação Proteica , Receptores de LDL/metabolismoRESUMO
Arylene bis(methylketone) compounds specifically block nuclear translocation of the HIV-1 pre-integration complex by forming Schiff-base adducts with contiguous lysines within nuclear localization signal.