Editors' ChoiceDrug Discovery

The Art of War on Viruses

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Science Translational Medicine  09 Jul 2014:
Vol. 6, Issue 244, pp. 244ec118
DOI: 10.1126/scitranslmed.3009804

Viruses have evolved clever ways to take over host cells. Host cells protect themselves by undergoing apoptosis (programmed death) after infections to prevent further viral spread. Sun Tzu, the author of The Art of War, wrote that “what is of supreme importance in war is to attack the enemy's strategy.” Indeed, viruses have developed ways to stop host cell death, allowing the virus to survive and persist. For example, the Epstein-Barr virus (EBV) can persist as a latent virus in human B cells and contribute to the development of human cancers, such as Burkitt’s lymphoma. To stop EBV persistence, Procko and colleagues designed a new protein that inhibits its “prosurvival” protein BHRF1.

BHRF1 is a homolog of the human prosurvival molecule B cell lymphoma-2 (Bcl-2), which blocks apoptosis. Bcl-2 works by sequestering certain proapoptotic proteins or by directly inhibiting apoptosis-initiating proteins. Viral BHRF1 prevents lymphocyte host death during infection by sequestering proapoptotic Bcl-2 homology 3 (BH3)–only proteins—especially one called Bim, which has been implicated in lymphomagenesis. Using computation-based protein design approaches, the investigators created de novo a potent inhibitor of BHRF1 with tight and specific binding activity. The functional motif of Bim-BH3 that promotes apoptosis (when bound to BHRF1) was “grafted” into a templated and structured three-helix bundle protein scaffold so as to achieve effective complementary target binding, proper folding, and stabilization. After scanning thousands of possible constructs, the authors narrowed down their choices to two engineered protein variants. Further manipulation by use of directed evolution yielded BHRF1 binder variants with even higher and stable affinity. The result was an artificially crafted protein that binds and inhibits BHRF1, thus triggering apoptosis in EBV-infected cancer cells in vitro. The engineered inhibitor suppressed tumor progression in animals with human EBV-positive lymphomas.

Key to success was the understanding of the enemy’s strategies and knowledge of basic protein structure and function. The computational template scaffolding and iterative optimization platform described by Procko et al. is a viable approach to generating new molecules that interfere with viral persistence in cancer. The next step is to address the intracellular and systemic delivery of such designer proteins in order to be able to use them clinically.

E. Procko et al., A computationally designed inhibitor of an Epstein-Barr viral Bcl-2 protein induces apoptosis in infected cells. Cell 157, 1644–1656 (2014). [Abstract]

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