Proteins and sugars league against HIV
CEA
The procedural conditions for synthesizing the molecule and its mechanism of action have been published online by Nature Chemical Biology.
Since the AIDS first broke out, some 60 million people have been infected with HIV — the virus proved fatal for half of them. With over two-dozen therapeutic agents engineered to date, there has been a strong increase in patient survival. However, most of these agents are targeted at virus replication within the cell, and none of them can eradicate the virus. Furthermore, the molecules developed entail major adverse effects that many patients find difficult to cope with, and these issues are compounded by the fact that cases of drug resistance are starting to flood in.
The development of new therapeutic strategies therefore hinges on refocusing research onto the virus itself.
Some of these strategies are aimed at blocking virus entry into cells. The glycoprotein gp120 anchored to the viral membrane could offer a first-line pharmacological target, since it is through gp120 that the virus is able to recognize a cell-surface receptor, CD4.
gp120 binding to CD4 induces a conformational** reshuffle that triggers the exposure of a new (CD4-induced) epitope site that is involved in the recognition of a second cell molecule (CCR5 or CXCR4) acting as a co-receptor***. This is the recognition gateway that enables the virus to enter the cell. The difficulty with using gp120 as a target lies in the fact that the site that needs to be blocked to enable the inhibition of viral entry only becomes accessible once the virus has already bound to CD4 and thus has already triggered the infection process.
gp120 binding to the cell’s CD4 receptor frees up a new recognition site. The gp120 protein can then bind to one of the co-receptors (CCR5 or CXCR4), creating the gateway needed for the virus to enter the cell.
Over the last few years, researchers at the Institute of Cell biology (‘IBS’) have been exploring the steps involved in HIV-host cell interactions from a different standpoint, by characterizing the interaction between the HIV gp120 and a third partner: Heparan sulphates (HS). Heparan sulphates are extremely complex polysulphate linear polysaccharides (sugars). They are found in abundance on the cell surface, and they present the remarkable property of being able to interact with a huge range of proteins, regulating their biological functions. Viruses like HIV, which willingly divert cell machinery to their own advantage, exploit the properties of HS in order to bind to the cell surface.
Building on previous research demonstrating that HS can be used to block co-receptor recognition domains and inhibit viral cell entry pathways, the IBS team has engineered a new molecule called CD4-HS. This compound binds to gp120 through CD4 to expose the co-receptor binding domain, making it accessible for HS to recognize and, consequently, to block (diagram below).
CD4-HS binding simultaneously blocks both gp120 recognition sites, inhibiting any interaction with either CD4 or the co-receptors. In other words, the virus can no longer enter the cell
Collaborative input from protein synthesis specialists from the Institut Pasteur, glycochemists from the ICMMO and biologists from the IBS has made it possible to synthetically engineer a miniaturized version of this compound and determine its mechanism of action. Baptized mCD4-HS12 (mini-CD4 bound to 12 HS sugar units), this molecule possesses the unique feature of simultaneously blocking the CD4-binder site and the co-receptor-binder site. Anti-viral activity tests conducted by SPI-Bio demonstrated that mCD4-HS12 is a highly efficient inhibitor of various HIV isolates ****.
This exceptional molecule, which prompted Nature Chemical Biology to publish its synthesis and mechanisms of action, offers numerous advantages: targeting two essential and conserved gp120 domains, advanced anti-viral attack, inhibition of viral entry regardless of the co-receptor gateway used (CXCR4 or CCR5). Research is now directed towards simplifying the structure and synthesis of mCD4-HS12. Next step: in vivo trials.