Search PubMed⌕ Search

Biomedical subjects

Mats Wahlgren

Publications and source records attributed to Mats Wahlgren.

23 records · Page 2Linked to original sources
PubMed2003

Design and synthesis of plasmepsin I and plasmepsin II inhibitors with activity in Plasmodium falciparum-infected cultured human erythrocytes.

A series of protease inhibitors targeted at the malarial enzymes plasmepsin I and II, and encompassing a basic hydroxyethylamine transition state isostere scaffold, was prepared. The substituents in the P1' position were varied and the biological activities expressed in K(i)-values ranged from 60 to >2000 nM. A more than 4-fold selectivity for either of the plasmepsins could be achieved. All of the active compounds exhibited high preference for the plasmepsins over cathepsin D, the most closely related human protease. A few active compounds were shown to inhibit parasite growth in cultured infected human erythrocytes. An ED(50) value as low as 1.6 microM was observed for one of the inhibitors despite K(i) values of 115 nM (Plm I) and 121 nM (Plm II).

Animals↗
PubMed2002

Heparan sulfate on endothelial cells mediates the binding of Plasmodium falciparum-infected erythrocytes via the DBL1alpha domain of PfEMP1.

Plasmodium falciparum may cause severe forms of malaria when excessive sequestration of infected and uninfected erythrocytes occurs in vital organs. The capacity of wild-type isolates of P falciparum-infected erythrocytes (parasitized red blood cells [pRBCs]) to bind glycosaminoglycans (GAGs) such as heparin has been identified as a marker for severe disease. Here we report that pRBCs of the parasite FCR3S1.2 and wild-type clinical isolates from Uganda adhere to heparan sulfate (HS) on endothelial cells. Binding to human umbilical vein endothelial cells (HUVECs) and to human lung endothelial cells (HLECs) was found to be inhibited by HS/heparin or enzymes that remove HS from cell surfaces. (35)S-labeled HS extracted from HUVECs bound directly to the pRBCs' membrane. Using recombinant proteins corresponding to the different domains of P falciparum erythrocyte membrane protein 1 (PfEMP1), we identified Duffy-binding-like domain-1alpha (DBL1alpha) as the ligand for HS. DBL1alpha bound in an HS-dependent way to endothelial cells and blocked the adherence of pRBCs in a dose-dependent manner. (35)S-labeled HS bound to DBL1alpha-columns and eluted as a distinct peak at 0.4 mM NaCl. (35)S-labeled chondroitin sulfate (CS) of HUVECs did not bind to PfEMP1 or to the pRBCs' membrane. Adhesion of pRBCs of FCR3S1.2 to platelet endothelial cell adhesion molecule-1 (PECAM-1)/CD31, mediated by the cysteine-rich interdomain region 1alpha (CIDR1alpha), was found be operative with, but independent of, the binding to HS. HS and the previously identified HS-like GAG on uninfected erythrocytes may act as coreceptors in endothelial and erythrocyte binding of rosetting parasites, causing excessive sequestration of both pRBCs and RBCs.

Animals↗
PubMed2002

Mosaic-like transcription of var genes in single Plasmodium falciparum parasites.

The var gene family of Plasmodium falciparum encodes the clonally variant adhesin PfEMP1 present on the surface of infected erythrocytes. A poorly understood mechanism of allelic exclusion controls the expression of PfEMP1. Transcription of var genes is developmentally and, most likely, epigenetically regulated. Here we have studied the transcriptional pattern of 28 members of this multigene family in individual parasites, early in the intraerythrocytic cycle. The results show unique patterns (type and number) of var transcripts in each individual PRBC, with 1-15 mRNA species detected per cell at 2-4 h post-invasion. When a panel of ten single PRBC was analyzed, the var gene coding for the expressed PfEMP1 was transcribed in more cells than any other, although transcripts from this gene did not give the strongest hybridization signal within each individual cell. Chromosomal mapping of transcriptionally active var genes indicated that their distribution reflects that of var loci in the genome, including a pronounced clustering in chromosome 4. These findings, taken together with existing data on var transcription at later developmental stages, suggest that the mosaic-like transcription of multiple var genes detected at the ring stage and the steady transcription of the gene encoding the expressed PfEMP1 are distinct although superimposed events, one of them random and the other taking place under some form of imprinting. With its unique features, the expression of P. falciparum var genes may reveal new principles of gene regulation.

Amino Acid Sequence↗