The attachment of
proteins to the cell membrane using a glycosylphosphatidylinositol
(GPI) anchor is a ubiquitous process in eukaryotic cells. Deficiencies
in the biosynthesis of GPIs and the concomitant production of GPI-anchored
proteins lead to a series of rare and complicated disorders associated
with inherited GPI deficiencies (IGDs) in humans. Currently, there
is no treatment for patients suffering from IGDs. Here, we report
the design, synthesis, and use of GPI fragments to rescue the biosynthesis
of GPI-anchored proteins (GPI-APs) caused by mutation in genes involved
in the assembly of GPI-glycolipids in cells. We demonstrated that
the synthetic fragments GlcNAc-PI (
1
), Man-GlcN-PI (
5
), and GlcN-PI with two (
3
) and three lipid
chains (
4
) rescue the deletion of the GPI biosynthesis
in cells devoid of the PIGA, PIGL, and PIGW genes in vitro. The compounds
allowed for concentration-dependent recovery of GPI biosynthesis and
were highly active on the cytoplasmic face of the endoplasmic reticulum membrane. These synthetic molecules are leads for the development
of treatments for IGDs and tools to study GPI-AP biosynthesis.