5lp1
From Proteopedia
CRYSTAL STRUCTURE OF HUMAN LIPOPROTEIN-ASSOCIATED PHOSPHOLIPASE A2 IN COMPLEX WITH A [1.1.1]BICYCLOPENTANE-CONTAINING INHIBITOR AT 1.91A RESOLUTION.
Structural highlights
DiseasePAFA_HUMAN Defects in PLA2G7 are the cause of platelet-activating factor acetylhydrolase deficiency (PAFAD) [MIM:614278. An enzymatic deficiency that results in exacerbated bodily response to inflammatory agents. Asthmatic individuals affected by this condition may manifest severe respiratory symptoms.[1] [2] [3] [4] [5] Defects in PLA2G7 are a cause of susceptibility to asthma (ASTHMA) [MIM:600807. The most common chronic disease affecting children and young adults. It is a complex genetic disorder with a heterogeneous phenotype, largely attributed to the interactions among many genes and between these genes and the environment. It is characterized by recurrent attacks of paroxysmal dyspnea, with weezing due to spasmodic contraction of the bronchi. Note=PLA2G7 variants can be a risk factor for the development of asthma and PLA2G7 may act as a modifier gene that modulates the severity of this disease.[6] Defects in PLA2G7 are a cause of susceptibility to atopic hypersensitivity (ATOPY) [MIM:147050. A condition characterized by predisposition to develop hypersensitivity reactions. Atopic individuals can develop eczema, allergic rhinitis and allergic asthma.[7] FunctionPAFA_HUMAN Modulates the action of platelet-activating factor (PAF) by hydrolyzing the sn-2 ester bond to yield the biologically inactive lyso-PAF. Has a specificity for substrates with a short residue at the sn-2 position. It is inactive against long-chain phospholipids. Publication Abstract from PubMedWe describe the incorporation of a bicyclo[1.1.1]pentane moiety within two known LpPLA2 inhibitors to act as bioisosteric phenyl replacements. An efficient synthesis to the target compounds was enabled with a dichlorocarbene insertion into a bicyclo[1.1.0]butane system being the key transformation. Potency, physicochemical, and X-ray crystallographic data were obtained to compare the known inhibitors to their bioisosteric counterparts, which showed the isostere was well tolerated and positively impacted on the physicochemical profile. Investigation of a Bicyclo[1.1.1]pentane as a Phenyl Replacement within an LpPLA2 Inhibitor.,Measom ND, Down KD, Hirst DJ, Jamieson C, Manas ES, Patel VK, Somers DO ACS Med Chem Lett. 2016 Nov 15;8(1):43-48. doi: 10.1021/acsmedchemlett.6b00281., eCollection 2017 Jan 12. PMID:28105273[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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