Chemical Synthesis of Glycosylphosphatidylinositol Anchors

Abstract

Many eukaryotic cell-surface proteins and glycoproteins are anchored to the plasma membrane by glycosylphosphatidylinositols (GPIs), a family of glycolipids that are post-translationally attached to proteins at their C-termini. GPIs and GPI-anchored proteins play important roles in many biological and pathological events, such as cell recognition and adhesion, signal transduction, host defense, and acting as receptors for viruses and toxins. Chemical synthesis of structurally defined GPI anchors and GPI derivatives is a necessary step toward understanding the properties and functions of these molecules in biological systems and exploring their potential therapeutic applications. In the first part of this comprehensive article on the chemical synthesis of GPIs, classic syntheses of naturally occurring GPI anchors from protozoan parasites, yeast, and mammals are covered. The second part of the article focuses on recent diversity-oriented strategies for the synthesis of GPI anchors containing unsaturated lipids, “click chemistry” tags, and highly branched and modified structures.

GPI-AP: Unraveling a New Class of Malignancy Mediators and Potential Immunotherapy Targets

“…Moreover, oxidation and reduction complexity affect the lipid tail. Such drawbacks were tackled by the use of modern blocking methods rather than global blocking (15,132). This resulted in the successful synthesis of naturally occurring GPI-AP and semisynthetic/synthetic derivatives containing unsaturated lipids (e.g., click chemistry tags), or highly branched structures (132).…”

“…Such drawbacks were tackled by the use of modern blocking methods rather than global blocking (15,132). This resulted in the successful synthesis of naturally occurring GPI-AP and semisynthetic/synthetic derivatives containing unsaturated lipids (e.g., click chemistry tags), or highly branched structures (132). In fact, a chemical method, designated one pot ligation (OPL), was used to achieve semisynthetic GPI anchored eGFP, Thy1, and the Plasmodium berghei protein MSP1 19 .…”

IgG antibodies to synthetic GPI are biomarkers of immune-status to both Plasmodium falciparum and Plasmodium vivax malaria in young children

“…It has been consistently demonstrated that GPIs purified from P. falciparum are recognized by plasma/serum from people living in malaria-endemic areas however, the quality of GPIs purified from P. falciparum might have led to controversial results [ 15 , 16 ]. Cross-reactivity between antibodies raised against P. falciparum GPI and P. vivax is expected, as despite having a high complexity that allows various chemical modifications and high functional diversity, the core of the GPI glycan structure is evolutionary highly conserved in different species [ 17 ]. Only limited structural variability (in fatty-acid composition or glycosylation) or antigenic variation have been described [ 18 – 21 ] in comparison to the many allelic polymorphisms identified in merozoite surface proteins [ 22 – 24 ], and the consequent high antigenic variation [ 25 – 27 ].…”

Toward the Development of the Next Generation of a Rapid Diagnostic Test: Synthesis of Glycophosphatidylinositol (GPI) Analogues of Plasmodium falciparum and Immunological Characterization

“…Unfortunately, isolating GPIs from the parasite in sufficient amounts with consistency and high purity is not a trivial endeavor. Fortunately, advances in glycan synthesis can generate extremely pure chemically defined complex glycoconjugates (human and parasite GPI anchors) in appreciable quantities. − Here, we present the design, synthesis of natural and pseudo-P. falciparum GPI analogues, generation of antibodies using GPI–protein conjugates, and initial immunological characterization.…”