Comparative levels of carbonyl delivery between mass-market cigars and cigarettes.

The recent 2016 deeming of cigars by the US Food and Drug Administration (FDA) has led to increased interest in cigar science, including ways to accurately measure the harmful and potentially harmful constituents (HPHCs) found within mainstream cigar smoke. At present, there are standardized methods for evaluating HPHCs in mainstream cigarette smoke but none specific to cigar analysis except for nicotine and carbon monoxide. This study sought to analyze carbonyl delivery in marketed cigars and cigarillos and compare them against levels found in cigarettes. To accomplish this the standard cigarette method, CORESTA recommended method 74 (CRM-74), was optimized for cigar smoking including an evaluation of the trapping efficiency and the stability of the carbonyl-hydrazone adducts due to the increased smoke time required for cigar collection. On a per product basis, carbonyl delivery from cigars smoked under CRM-64 conditions was found to yield similar levels of formaldehyde and greater levels of acetaldehyde, acrolein and crotonaldehyde than measured in mainstream cigarette smoke collected under conditions prescribed under ISO standard 3308. Furthermore, on a per product basis, cigarettes smoked under the ISO 20778 intense smoking regime delivered higher levels of formaldehyde, acrolein and crotonaldehyde as compared to cigars smoked under the CORESTA regime, while acetaldehyde was found to be higher in mainstream cigar smoke. Given the recent deeming, this work expands upon previously reported work, limited in scope by either number of products or analytes reported, through the analysis of carbonyl delivery found in the mainstream smoke for 12 brands of cigars and cigarillos.

Design, synthesis, and evaluation of novel small molecule inhibitors of the influenza virus protein NS1.

Influenza is a continuing world-wide public health problem that causes significant morbidity and mortality during seasonal epidemics and sporadic pandemics. The existing vaccination program is variably effective from year to year, and drug resistance to available antivirals is a growing problem, making the development of additional antivirals an important challenge. Influenza virus non-structural protein 1 (NS1) is the centerpiece of the viral response to the host interferon (IFN) system. NS1 was demonstrated previously to be a potential therapeutic target for antiviral therapy by the identification of specific small-molecule inhibitors. One inhibitory compound, NSC125044, was subjected to chemical evaluation. Initial synthetic work comprised simplifying the core structure by removing unwanted functionality and determination of key features important for activity. Several subclasses of molecules were designed and synthesized to further probe activity and develop the basis for a structure-activity relationship. Apparent potency, as judged by activity in virus replication assays, increased dramatically for some analogs, without cytotoxicity. Results suggest that the target binding site tolerates hydrophobic bulk as well as having a preference for weakly basic substituents.

Novel inhibitor of influenza non-structural protein 1 blocks multi-cycle replication in an RNase L-dependent manner.

Influenza virus non-structural protein 1 (NS1) is the centrepiece of the viral response to the host interferon (IFN) system. NS1 has been demonstrated previously to be a potential therapeutic target for antiviral therapy by identification of specific small-molecule inhibitors. This study demonstrated the biological mechanism for a potent new NS1 antagonist. Compound JJ3297 inhibited virus replication by more than three orders of magnitude without affecting cell viability. Importantly, it efficiently reversed NS1-induced inhibition of IFN mRNA production. The hypothesis was tested that JJ3297 facilitates IFN production in infected cells, leading to protection of the surrounding uninfected cells. Accordingly, the compound efficiently prevented virus spread through a cell population during a 48 h multi-cycle infection initiated at a very low m.o.i. Consistent with the hypothesis, the compound had no detectable influence on a 6 h single-cycle infection initiated at a high m.o.i. The effect of JJ3297 on virus replication was not caused by inhibition of NS1 expression or its mislocalization in the cell. JJ3297 facilitated the induction of an IFN-like antiviral state, resulting in increased resistance to subsequent challenge with vesicular stomatitis virus. The activity of JJ3297 absolutely required the function of cellular RNase L, indicating that an intact IFN system is required for function of the compound. These results support a model in which inhibition of NS1 function results in restoration of the IFN-induced antiviral state and inhibition of virus replication and spread. This represents a new direction for anti-influenza virus drug development that exploits the IFN pathway to challenge virus replication.