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X-RAYS PROVE THE EFFICACY OF A PROTEIN WITH POTENTIAL TO INHIBIT HIV-1

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Using hard X-rays of the ALBA Synchrotron, a group of researchers have solved the crystal structure of rationally designed single-chain protein constructs that can prevent HIV-1 infection.

The glycoprotein gp41 takes part of the envelope of the human immunodeficiency virus (HIV) and it is responsible of the virus fusion to the host cell membrane. During HIV-1 infection, two regions of the envelope subunit gp41 (the N-terminal and C-terminal heptad repeats, NHR and CHR) can temporarily be accessible to inhibitors.

Researchers have designed single-chain protein constructs that mimic the NHR surface and bind to synthetic CHR peptides. Furthermore, the constructs block the HIV-1 fusion, preventing the virus to bind and infect the host cell membrane, as shown by the broad inhibitory activity of HIV-1 fusion on various pseudoviruses and primary isolates. Next step was growing the protein constructs in crystals to expose them to the X-rays produced at ALBA.

X-ray diffraction experiments were performed at XALOC beamline to solve the crystal structure of the protein constructs, confirming their capacity to mimic NHR surface of gp41.

These proteins, that are highly stable and with accurate mimicking properties, have a strong potential for the development of HIV-1 drugs, vaccines or microbicides.

This research has been conducted by members of the University of Granada, the University of Almería, PX Therapeutics, Sanofi Pasteur and INSERM, with funds from the Euroneut-41 grant of the VII Framework Programme of the European Union and the Andalusia Regional Government.

X-rays prove the efficacy of a protein with potential to inhibit HIV-1

Fig. Crystallographic structure of the protein construct. Representation of the superposition of the protein construct onto the theoretical model of the gp41 ectodomain.

Reference: "Single-chain protein mimetics of the N-terminal heptad-repeat region of gp41 with potential as anti-HIV-1 drugs" Sara Crespillo, Ana Cámara-Artigas, Salvador Casares, Bertrand Morel, Eva S. Cobos, Pedro L. Mateo, Nicolas Mouz, Christophe E. Martin, Marie G. Roger, Raphaelle El Habib, Bin Su, Christiane Moog, Francisco Conejero-Lara. PNAS 111 (51) (2014) 18207–18212, doi: 10.1073/pnas.1413592112


HIV is still a problem

HIV-1 is the most common and pathogenic strain of the human immunodeficiency virus. AIDS continues to be a global public health issue, having claimed more than 39 million lives so far, according to the World Health Organization (WHO). Sub-Saharan Africa is the most affected region, with 24.7 million people living with HIV in 2013. Also sub-Saharan Africa accounts for almost 70% of the global total of new HIV infections.

No effective vaccine against HIV has been developed yet. However effective treatment with antiretroviral (ARV) drugs can control the virus. Nevertheless, current treatments, like T20 drug, present some disadvantages such as the need of high doses, adverse effects, appearance of resistance and a high cost. Therefore, new improved compounds are still necessary to increase the existing arsenal to treat and prevent HIV-1 infection.



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