Host factors involved in viral replication are potentially attractive antiviral targets that are complementary to specific inhibitors of viral enzymes, since resistant mutations against the latter are likely to emerge during long-term treatment. It has been reported recently that cyclosporine, which binds to a family of cellular proteins, cyclophilins, inhibits hepatitis C virus (HCV) replication in vitro. Here, the activities of various cyclosporine derivatives were evaluated in the HCV replicon system. There was a strong correlation between the anti-HCV activity and cyclophilin-binding affinity of these compounds. Of these, NIM811 has been selected as a therapeutic candidate for HCV infection, since it binds to cyclophilins with higher affinity than cyclosporine but is devoid of the significant immunosuppressive activity associated with cyclosporine. NIM811 induced a concentration-dependent reduction of HCV RNA in the replicon cells with a 50% inhibitory concentration of 0.66 M at 48 h. Furthermore, a greater than three-log 10 viral RNA reduction was achieved after treating the cells with as little as 1 M of NIM811 for 9 days. In addition, the combination of NIM811 with alpha interferon significantly enhanced anti-HCV activities without causing any increase of cytotoxicity. Taken together, these promising in vitro data warrant clinical investigation of NIM811, an inhibitor of novel mechanism, for the treatment of hepatitis C.

In breast cancer, estrogen receptor alpha (ERα) positive cancer accounts for approximately 74% of all diagnoses, and in these settings, it is a primary driver of cell proliferation. Treatment of ERα positive breast cancer has long relied on endocrine therapies such as selective estrogen receptor modulators, aromatase inhibitors, and selective estrogen receptor degraders (SERDs). The steroid-based anti-estrogen fulvestrant (5), the only approved SERD, is effective in patients who have not previously been treated with endocrine therapy as well as in patients who have progressed after receiving other endocrine therapies. Its efficacy, however, may be limited due to its poor physicochemical properties. We describe the design and synthesis of a series of potent benzothiophene-containing compounds that exhibit oral bioavailability and preclinical activity as SERDs. This article culminates in the identification of LSZ102 (10), a compound in clinical development for the treatment of ERα positive breast cancer.

The respiratory syncytial virus (RSV) L protein is a viral RNA-dependent RNA polymerase that contains multiple enzyme activities required for RSV replication. The RSV L inhibitors described in literature are limited by their cytotoxicity or the lack of RSV B subtype coverage. Here, we characterize a new RSV L inhibitor with strong antiviral activity against both RSV A and B subtypes and no detectable cytotoxicity. This compound, AZ-27, was equally active against RSV live viruses and subgenomic replicons and demonstrated advantages over other classes of RSV inhibitors in time-of-addition and cell line dependency studies. Resistance studies identified a dominant mutation in the putative capping enzyme domain of L protein, which conferred strong resistance to the AZ-27 series but not other classes of RSV inhibitors, supporting RSV L protein as the direct target for AZ-27. This novel and broad-spectrum RSV L polymerase inhibitor may pave the way toward an efficacious RSV therapeutic and provide a new tool for interrogation of the L protein function. R espiratory syncytial virus (RSV) is an enveloped, nonsegmented negative-sense RNA virus in the Paramyxoviridae family. RSV infection is ubiquitous in that virtually everyone is infected by the age of 2 years and reinfection occurs throughout all ages. It is the leading cause of acute lower respiratory tract infections in young children, the elderly, and immunosuppressed patients (1). Progress has been made toward vaccine development, but many challenges remain, as highlighted by the short-lived natural immune response against RSV with high reinfection rate, the difficulty in eliciting a protective immune response in neonates, and the unexpected enhancement of disease by RSV vaccination observed in the formalin-inactivated RSV vaccine trial (2). Immunoprophylaxis with RSV-neutralizing antibodies has been successful in protecting high-risk infants and children. However, there is no RSV-specific therapy available for postinfection treatment, and RSV continues to be the number one reason for infant hospitalization (3). The only approved treatment for RSV is ribavirin, which has limited clinical utility due to its high toxicity and controversial efficacy (4). Therefore, finding an effective treatment for RSV infection remains an important public health priority.The limited understanding of the molecular mechanisms of RSV replication and pathogenesis has hampered the development of RSV therapeutics (5). RSV replication requires the viral RNA genome, mRNAs, 11 viral proteins, and many host factors, all of which are potential targets for therapeutic intervention. Targeting host factors holds the promise of broader-spectrum coverage and a potentially higher barrier to resistance. However, there may also be on-target toxicity, the adverse pharmacologic effect of interfering with a cellular target important for host function, which would be of particular concern in treating young infants, the main population affected by severe RSV diseases. Antivirals directly targeting viral pro...

No abstract

No abstract