Drug Discovery Opinion

Kaposi’s sarcoma (KS) is caused by Kaposi sarcoma herpes virus (KSHV) which is also known as human herpes virus 8 (HHV8). HHV8 infection rates vary widely amongst different populations but KS rarely develops unless the immune system is compromised, by AIDS, transplant drugs, or ageing. There is currently no specific treatment for KS but researchers at UCSF have now identified small molecules that target the viral protease. Along with other members of the herpes family of viruses – including herpes simplex viruses I and II, varicella zoster virus, cytomegalovirus and Epstein-Barr virus – HHV8 encodes a serine protease that is essential for viral capsid formation and viral replication. Many previous attempts to discover inhibitors of herpes virus proteases targeting the active site of the enzymes met with limited success, perhaps because of difficulty in finding molecules that bind tightly to the shallow substrate-binding cleft. The UCSF team have chosen instead to inhibit catalytic activity by disrupting dimerisation of the enzyme.

A number of earlier studies have shown that dimerisation is a common mechanism for activation of herpes virus proteases, and the UCSF team have previously identified a helical peptide that prevents dimerisation of herpes virus proteases. In the new study, published online in the journal Nature Chemical Biology, the team describe small molecules, including DD2, which inhibit dimerisation of both HHV8 and CMV proteases with IC₅₀s in the low micromolar range.

HIV protease also acts as an obligate dimer but, in this case, dimerisation inhibitors have been less successful than compounds that directly target the active site, many of which are now in clinical use. The difficulties experienced in trying to identify active site inhibitors of the herpes virus serine proteases may mean that disruption of dimerisation presents a more attractive target for these challenging enzymes.

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