•Optimization and preclinical analysis of a bacterial natural product•Combination of bioengineering and semisynthetic chemistry•Preclinical analysis revealing potent antiviral activityInhibition of host-encoded targets, such as the cyclophilins, provides an opportunity to generate potent high barrier to resistance antivirals for the treatment of a broad range of viral diseases. However, many host-targeted agents are natural products, which can be difficult to optimize using synthetic chemistry alone. We describe the orthogonal combination of bioengineering and semisynthetic chemistry to optimize the drug-like properties of sanglifehrin A, a known cyclophilin inhibitor of mixed nonribosomal peptide/polyketide origin, to generate the drug candidate NVP018 (formerly BC556). NVP018 is a potent inhibitor of hepatitis B virus, hepatitis C virus (HCV), and HIV-1 replication, shows minimal inhibition of major drug transporters, and has a high barrier to generation of both HCV and HIV-1 resistance.

Chronic hepatitis C virus (HCV) infection results in a progressive disease that may end in cirrhosis and, eventually, in hepatocellular carcinoma. In the last several years, tremendous progress has been made in understanding the HCV life cycle and in the development of small molecule compounds for the treatment of chronic hepatitis C. Nevertheless, the complete understanding of HCV assembly and particle release as well as the detailed characterization and structure of HCV particles is still missing. One of the most important events in the HCV assembly is the nucleocapsid formation which is driven by the core protein, that can oligomerize upon interaction with viral RNA, and is orchestrated by viral and host proteins. Despite a growing number of new factors involved in HCV assembly process, we do not know the three-dimensional structure of the core protein or its topology in the nucleocapsid. Since the core protein contains a hydrophobic C-terminal domain responsible for the binding to cellular membranes, the assembly pathway of HCV virions might proceed via coassembly at endoplasmic reticulum membranes. Recently, new mechanisms involving viral proteins and host factors in HCV particle formation and egress have been described. The present review aims to summarize the advances in our understanding of HCV assembly with an emphasis on the core protein as a structural component of virus particles that possesses the ability to interact with a variety of cellular components and is potentially an attractive target for the development of a novel class of anti-HCV agents.

With the approval in 2011 of the protease inhibitors Victrelis and Incivek, direct-acting antivirals have begun to revolutionize HCV treatment. Although the addition of Incivek or Victrelis to PEGylated IFNα and ribavarin (pIFNα/RBV) may improve cure rates and shorten the treatment duration of the “old” standard of care (SOC), this triple therapy will not be suitable for patients intolerant to pIFNα or RBV. The efficacy of this triple therapy will also certainly be attenuated in pIFNα/RBV non-responders. As Incivek is inactive against genotype 3 (GT3) combined with the fact that all protease inhibitors and most of the non-nucleoside polymerase inhibitors in development are active primarily against GT1, pIFNα/RBV will remain the SOC for non-GT1 until new classes of inhibitors enter into clinical practice. GT1 patients who do not respond to this new triple therapy will have developed resistance to protease inhibitors that will limit future treatment options. There is thus an important need for the identification of new potent HCV agents. A novel class of HCV inhibitors that have great potential for the treatment for HCV has recently emerged: the host-targeting antivirals cyclophilin inhibitors.

In the absence of an effective vaccine, there is an urgent need for safe and effective antiviral agents to prevent transmission of HIV. Here, we report that an amphipathic α-helical peptide derived from the hepatitis C virus NS5A anchor domain (designated C5A in this article) that has been shown to be virocidal for the hepatitis C virus (HCV) also has potent antiviral activity against HIV. C5A exhibits a broad range of antiviral activity against HIV isolates, and it prevents infection of the three in vivo targets of HIV: CD4+ T lymphocytes, macrophages, and dendritic cells by disrupting the integrity of the viral membrane and capsid core while preserving the integrity of host membranes. C5A can interrupt an ongoing T cell infection, and it can prevent transmigration of HIV through primary genital epithelial cells, infection of mucosal target cells and transfer from dendritic cells to T cells ex vivo, justifying future experiments to determine whether C5A can prevent HIV transmission in vivo.

Dendritic cells (DCs) efficiently capture HIV-1 and mediate transmission to T cells, but the underlying molecular mechanism is still being debated. The C-type lectin DC-SIGN is important in HIV-1 transmission by DCs. However, various studies strongly suggest that another HIV-1 receptor on DCs is involved in the capture of HIV-1. Here we have identified syndecan-3 as a major HIV-1 attachment receptor on DCs. Syndecan-3 is a DC-specific heparan sulfate (HS) proteoglycan that captures HIV-1 through interaction with the HIV-1 envelope glycoprotein gp120. Syndecan-3 stabilizes the captured virus, enhances DC infection in cis, and promotes transmission to T cells. Removal of the HSs from the cell surface by heparinase III or by silencing syndecan-3 by siRNA partially inhibited HIV-1 transmission by immature DCs, whereas neutralizing both syndecan-3 and DC-SIGN completely abrogated HIV-1 capture and subsequent transmission. Thus, HIV-1 exploits both syndecan-3 and DC-SIGN to mediate HIV-1 transmission, and an effective microbicide should target both syndecan-3 and DC-SIGN on DCs to prevent transmission.