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A Landmark Discovery Guiding Future Drug Design—Scientists Reveal How HIV Infects Cells

Since 32 year ago, when the first HIV case appeared, humans have never slowed down the paces in HIV research. Recently, Scientists from The Shanghai Institute of Materia Medica (SIMM) and The Scripps Research Institute (TSRI) in California achieved a breakthrough in this area, successfully revealing the mechanism of Maraviroc, an anti-HIV drug. This new finding was published on recent Science Express.

This study was directed by Beili Wu, PhD, professor at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences. Wu and co-workers utilized protein crystallography techniques to obtain the high-resolution three-dimensional atomic structure of a cell-surface receptor, CCR5, which is very helpful for understanding of how HIV infects cells. SIMM has started the process drug design according to these results and it is in good progress.

During the early stage of HIV infecting host cells, CCR5 is a key receptor protein. The previous research revealed that people with mutant CCR5 protein are immune from HIV infection and this drew a lot attention on the function of CCR5. The researchers hoped to develop drugs that can restrain the biological activity of CCR5, so that they could stop the HIV infection on cells. However, a few amounts of drugs restraining CCR5 bioactivity have come into use, though, the specific mechanism has not been demonstrated clearly.

The researchers once tried to determine the functional area of CCR5 receptor by mutating its key sites. While in this research, the researchers used molecular imaging technique to locate the binding site pocket between Maraviroc and CCR5. The results indicated that the binding site between Maraviroc and CCR5 is different from all known binding sites of HIV and natural receptors, suggesting that Maraviroc does not influence the HIV infection process through competitive inhibition. Further study demonstrated that Maraviroc could alter the molecular conformation of CCR5 and keep it at inactive status, so that HIV can’t recognize and bind with it and thus, prevent HIV from infecting cells.

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An image showing the binding sites between CCR5 protein (blue carbon chains) and Maraviroc (orange carbon chains). Image source: Qiuxiang Tan,et al.(2013)Science.

In addition, the researchers also analyzed the structure of another cell-surface receptor protein, CXCR4, which is a similar receptor to CCR5 and is generally thought to be a required protein during the later period of HIV infection. Through crystallography and comparison, scientists found that HIV’s selectivity on receptors might rely on the subtle differences in surface charge distributions and shapes between these two proteins. These results are helpful in further demonstration on details about how HIV infects cells and push forward the drug design process.

Beili Wu noted that she and her colleagues plan to follow up with structural studies of CCR5 and CXCR4 in complex with the HIV envelope proteins CD4 and gp120 to obtain even more informative pictures of the process of viral infection.

ReferenceTan Q., et al. (2013) Structure of the CCR5 Chemokine Receptor–HIV Entry Inhibitor Maraviroc Complex. Science.

Source:Eurekalert!

Image sourceShutterstock 

 

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