Is there a new class of anti-HIV drugs on the horizon?

At present,  the recommended therapy for HIV/AIDS involves a combination of several antiretroviral drugs (ARVs) in highly active antiretroviral therapy (HAART)1. The toxicity of certain ARVs and the emergence of drug-resistant viral strains present great challenges in the treatment of HIV/AIDS and heighten the need for safer, more efficacious compounds2.  In spirit of this pursuit, a recent study has used atomistic simulation to study the dimerisation of HIV-1 protease, a viral enzyme targeted by a class of ARVs called ‘protease inhibitors’, or PIs. First used in clinical practice in 19951, PIs  have been shown to improve virus suppression and dramatically reduce mortality and morbidity in patients3. In fact, combination antiretroviral therapy combined with PIs has proven to be most beneficial when compared with other mono- and combination therapies3.

During replication, the HIV virus synthesizes a long string of proteins- a ‘polyprotein’- which assembles the immature form of the virus4. HIV-1 protease then cleaves the polyprotein at several distinct sites1, leaving the functional proteins that form the mature, infective virion. Precise timing of this process is crucial, and disruption could hinder the virus’s ability to infect new cells4.  It is both the sensitivity and the crucial nature of this process that make HIV-1 protease such a valuable target for ARVs1,4.

 

 

All current FDA-approved PIs are competitive inhibitors, which reduce HIV infectivity by blocking the active site of key viral enzymes5. This common mode of action is problematic, as drug-resistant viral variants may demonstrate cross-resistance across the entire class of drugs, thus reducing the number of alternatives available5. Consequently, researchers are now searching for molecules that interfere with the protein-protein interactions within enzymes, rather than those that target the active site2.

 

A figure presenting the structure of HIV-1 protease, including the enzymatic pocket and flap tips (Pietrucci et al., 2015)

Figure 1. A figure presenting the structure of HIV-1 protease, including the enzymatic pocket and flap tips (Pietrucci et al., 2015)

HIV-1 protease comprises two identical protein chains which assemble to form a long tunnel, or ‘enzymatic pocket’, concealed by two flexible protein flaps as shown in figure 1. The active site is located in the centre of this tunnel, where protein chains are bound and broken apart4. While studying the dimerisation mechanism of the enzyme through atomistic simulation, Pietrucci et al. (2015) discovered a transient binding pocket at the interface of the complex formed by the enzyme’s protein chains. It was reported that this binding pocket exhibited “favourable druggability features”, i.e. the pocket’s size and amino acid composition seem suitable for binding to small molecule drugs ,and may provide the ground work for further investigations into designing a new class of PI altogether2. While more extensive work is required to identify inhibitors that could target this new site2, the finding certainly provides valuable insight to the quest for alternative HIV therapies.

Bibliography

  1. Weber, I. T. & Agniswamy, J. HIV-1 protease: Structural perspectives on drug resistance. Viruses 1, 1110–1136 (2009).
  2. Pietrucci, F., Vargiu, A. V. & Kranjc, A. HIV-1 Protease dimerization dynamics reveals a transient druggable binding pocket at the interface. Sci. Rep. 5, 18555 (2015).
  3. Palella, F. J. et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N. Engl. J. Med. 338, 853–860 (1998).
  4. Goodsell, D. S. HIV-1 Protease. RCSB Protein Data Bank (2000). doi:10.2210/rcsb_pdb/mom_2000_6
  5. Yang, H., Nkeze, J. & Zhao, R. Y. Effects of HIV-1 protease on cellular functions and their potential applications in antiretroviral therapy. Cell Biosci. 2, 32 (2012).

Featured image source: Gross L (2006) Reconfirming the Traditional Model of HIV Particle Assembly. PLoS Biol 4(12): e445. doi:10.1371/journal.pbio.0040445

 

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Rachel Stevens

Rachel Stevens

I'm a Biology graduate with an interest in human biology, public health and scientific communications. Before beginning in medical communications, I also gained some laboratory work experience in biological control and in molecular neurobiology during and after my degree, respectively. I am hoping this will be a fun way of improving my writing skills and a great way to be informed of the latest scientific news. Thanks for stopping by and taking a look!
Rachel Stevens

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