Synthetic neoglycoconjugates of cell-surface phosphoglycans of Leishmania as potential anti-parasite carbohydrate vaccines

Abstract

Leishmania are a genus of sandfly-transmitted protozoan parasites that cause a spectrum of debilitating and often fatal diseases in humans throughout the tropics and subtropics. During the parasite life cycle, Leishmania survive and proliferate in highly hostile environments. Their survival strategies involve the formation of an elaborate and dense cell-surface glycocalyx composed of diverse stage-specific glycoconjugates that form a protective barrier. Phosphoglycans constitute the variable structural and functional domain of major cell-surface lipophosphoglycan and secreted proteophosphoglycans. In this paper, we discuss structural aspects of various phosphoglycans from Leishmania with the major emphasis on the chemical preparation of neoglycoconjugates (neoglycoproteins and neoglycolipids) based on Leishmania lipophosphoglycan structures as well as the immunological evaluation for some of them as potential anti-leishmaniasis vaccines. KeywordsLeishmania; lipophosphoglycan; carbohydrates; neoglycoconjugates; glycoconjugate vaccines; chemical synthesis Leishmania are a genus of sandfly-transmitted protozoan parasites that cause a spectrum of debilitating and often fatal diseases in humans throughout the tropics and subtropics. The disease (termed leishmaniasis) torments over 12 million people worldwide, making 2.4 million people disabled and causing about 60,000 deaths annually. The WHO estimations show that 350 million people are thought to be at risk from the disease [1][2][3]. Although leishmaniasis is most common in tropical regions, it has also been diagnosed in overseas travelers and U.S. Gulf War veterans [4] and has emerged as an opportunistic infection of HIV patients [5]. The geographical distribution and pathology of leishmaniasis varies according to the species of the parasite. For instance, Leishmania donovani causes "visceral leishmaniasis" (also known as kala azar), characterized by an enlarged liver and spleen, that is often fatal, whereas L. major and L. tropica (in the Old World) and L. mexicana species

An α-Gal-containing neoglycoprotein-based vaccine partially protects against murine cutaneous leishmaniasis caused by Leishmania major

“…Carbohydrates have been proposed as potential targets for vaccines against Leishmania spp. [ 32 , 67 ]. Vaccination with Leishmania lipophosphoglycan (LPG), one of the major components of the glycocalyx of the parasite, revealed contradictory results [ 68 – 70 ].…”

Recent Progress in the Synthesis of Glycosyl Phosphate Derivatives

“…Currently, such complex molecules are generally synthesized by the H-phosphonate method (1,4,8). Figure 4 shows as an example the reaction cycle for the synthesis of a fragment of the extracellular phosphomannan from Hansenula capsulata Y-1842 19 (29).…”

“…Chemically modified analogs of these glycosyl donors are used as probes and inhibitors against the biosynthetic pathways of the oligosaccharides (15,16). Chemically synthesized glycosyl phosphate derivatives have become indispensable for all of these studies (1,4,5,8,10). Chemical synthesis of biomolecules is generally advantageous over methods using isolation of those from living organisms in terms of producing sufficient quantities of pure compounds at low costs.…”

“…Because these polysaccharides and glycoconjugates define the immunological specificity of the parent microorganism, the primary constituent phosphoglycans have been studied as potential vaccines, particularly against virulent species such as Neisseria meningitidis, Streptococcus pneumoniae, and Leishmania ( Fig. 1) (2)(3)(4)(5). In fact, the CPSs isolated from N. meningitidis and S. pneumoniae as well as their conjugates with proteins are used as vaccines (2,3).…”

Detecção de antígenos circulantes como abordagem diagnóstica em leishmaniose visceral.

“…As moléculas mais abundantes no glicocálice de Leishmania spp. é o LPG (Nikolaev, Sizova, 2011) e a gp63 (Olivier et al, 2005), as quais influenciam diretamente para a virulência do parasito. Essas moléculas apresentam variáveis níveis de expressão relacionados aos estágios morfológicos do parasito, vale ressaltar que a expressão é diminuída em amastigotas (McConville et al, 1995).…”