Validation of a RSK-inhibitor as a Novel Therapeutic for

DESCRIPTION (provided by applicant): The inactivation of the host immune response by Yersinia, the causative agent of the plague, is mediated by a family of six proteins called Yersinia outer proteins, or Yops, namely YopE, YopH, YopO, YopM, YopJ, and YopT. While the mechanisms of action of YopE, YopH, YopO, YopJ, and YopT are fairly well understood, the effects of YopM on the host response to Yersinia infection remain largely uncharacterized. It is believed that YopM inhibits the secretion of cytokines from host cells, thereby preventing the recruitment of the host nonspecific immune response to sites of infection. However, recent studies have demonstrated the direct interaction of YopM with two intracellular targets, ribosomal S6 protein kinase 1 (RSK1) and protein kinase C-like 2 (PRK2). The association of RSK1 and PRK2 with YopM results in a novel complex that could potentially be responsible for inactivating the host immune response via a unique signaling pathway. The Luna Innovations/University of Virginia research team has discovered identified and characterized the only known specific inhibitor of RSK in vitro and in vivo. Using this inhibitor, SL0101, the Luna Innovations/University of Virginia research team propose to assess the feasibility of RSK as a YopM target during Yersinia infection, and SL0101 as a potential therapeutic agent to either prevent or reverse the effects of Yersinia infection on the host immune response. The focus of the Phase I program is to study the effects of SL0101 on the activity of the YopM/PRK2/RSK1 complex, and on cytokine production and secretion in macrophage cells infected with Yersinia. The recent identification of Yersinia strains resistant to multiple drugs, and its potential use as a biological warfare agent, mean that plague still poses a major threat to humans, and has been classified by the Center for Disease Control (CDC) as a Category A agent. Therefore, there exists an important need to identify novel methods of combating this threat to human health.