HIV: Preventing entry into the cell

Since the start of the AIDS epidemic, nearly 80 million people have been infected with HIV and 35 million people have died from it. The launch of many therapeutic molecules and their combinations has significantly increased patient survival rates. However, none of them can eradicate the virus, which can mutate to become resistant to the medication used. Therefore, exploring new therapeutic strategies remains a research priority in HIV.

A glycoconjugate with demonstrated anti-viral activity

The first validated therapeutic targets leading to effective treatment were enzymes involved in an HIV replication stage in already infected cells. With the launch of Enfuvirtide and Maraviroc, the inhibition of HIV entry into its target cells, has more recently emerged as a promising approach, despite initial failure.

The HIV entry mechanism involves two viral proteins (gp120 and gp41), as well as two proteins on the host cells’ surface: the CD4 receptor and a co-receptor (CXCR4 or CCR5). A sulphated linear polysaccharide (heparan sulphate: HS), which is not as well-known as the two preceding proteins, but is no less important, plays a role in the infection process.

A French consortium involving a team from the Orsay Institute of Molecular Chemistry and Materials - ICMMO (Paris-Sud/CNRS),[1] proposed validating a novel strategy aiming to simultaneously block the interaction of gp120 with three key actors in the entry mechanism: the receptor, co-receptors and HS chains. To do this, the teams designed and synthesised the CD4-HS molecule: a functional mimic of the CD4 receptor linked to a synthetic HS dodecamer. CD4-HS has exceptional anti-viral activity in vitro and researchers have demonstrated that it blocked the HIV cleavage sites on the host cell surface, preventing access to the inside of cells according to the predicted mechanism.[2] The next step was to establish evidence of the therapeutic activity of this molecule in an in-vivo study. A compound with a peptide-like polyanion, even more active than CD4-HS, was selected during a molecular optimisation procedure.[3] The latter demonstrated excellent protective power during a viral challenge on macaque vaginal mucosa.[4] This study thus demonstrated that use of the optimised molecule could be considered for preventive purposes and confirmed the potential of the approach developed for the chronic treatment of infected patients.

Glycoscience and therapeutic innovation

Sucrose or starch are eaten... and end up as glucose, the energy source of all our cells. Many simple sugars (glucose, fructose, galactose, etc.) can also be the building blocks of more complex molecules: polysaccharides. These molecules on the cell surface play a crucial role in communication between cells and the extracellular medium. They enable specific interactions based on the classic “lock and key” model. Nature has three alphabets: one for proteins, one for nucleic acids and one for polysaccharides. The objective of glycoscience is to decipher the meaning of the latter. The chemists’ expertise then makes it possible to control the “lock and key” interactions by manufacturing pieces of polysaccharides with the right shape and structure, to be recognised by the targeted protein. At ICMMO, the Glycosaminoglycan and Molecular Diversity Group in the Methodology, Synthesis and Therapeutic Molecule Team is developing novel and effective synthesis methods, particularly in the field of heparan sulphates. This type of glycosaminoglycan, involved in many pathophysiological processes, offers great potential in therapeutic innovation. This field of investigation is explored in the context of interdisciplinary collaborations, particularly with LabEx LERMIT.

Acknowledgements:
This research was carried out with support from ANRS (National Agency for AIDS and Viral Hepatitis Research), Fondation Pierre Bergé-Sidaction and the ANR (National Research Agency).

References:
[1]    Institut de Chimie Moléculaire et des Matériaux d’Orsay (ICMMO), UMR 8182, LabEx LERMIT, Univ Paris Sud, CNRS, Université Paris-Saclay, Orsay, France. Institut Pasteur, UMR CNRS 3569, Paris, France. Institut de Biologie Structurale, UMR5075 CNRS, CEA, Université Grenoble-Alpes, 38027 Grenoble, France.

[2]    A synthetic CD4-HS glycoconjugate inhibits both CCR5 and CXCR4 HIV-1 attachment and entry. Baleux F., Loureiro-Morais L., Hersant Y., Clayette P., Arenzana-Seisdedos F., Bonnaffé D. Lortat-Jacob H. Nature Chem. Biol. 2009, 5 (10), 743-748.

[3]    A synthetic heparan sulfate-mimetic peptide conjugated to a mini CD4 displays very high anti-HIV-1 activity independently of coreceptor usage. B. J. Connell, F. Baleux, Y-M. Coic, P. Clayette, D. Bonnaffé, H. Lortat-Jacob, Chemistry and Biology, 2012, 19, 131-139.

[4]    CD4-mimetic sulfopeptide conjugates display sub-nanomolar anti-HIV-1 activity and protect macaques against a SHIV162P3 vaginal challenge. K-K. Arien, F. Baleux, D. Desjardins, F. Porrot, Y-M. Coïc, J. Michiels, K. Bouchemal, D. Bonnaffé, T. Bruel, O. Schwartz, R. Le Grand, G. Vanham, N. Dereuddre-Bosquet, H. Lortat-Jacob, Sci. Rep. 2016, 6, article number 34829, DOI: 10.1038/srep34829.

Contact:
David Bonnaffé
ICMMO UMR 8182
Methodology, Synthesis and Therapeutic Molecules Team
Glycosaminoglycan and Molecular Diversity Group  
LabEx LERMIT
Tel 01 69 15 72 33
david.bonnaffe @ u-psud.fr