SULFUR-CONTAINING COMPOUNDS AS HYDROGEN SULFIDE  AND BROAD-SPECTRUM ANTIVIRAL  AGENTS

Armando Pacheco

Hydrogen sulfide (H2S) is a signaling molecule which plays regulatory roles in many physiological and/or pathological processes. Therefore, regulation of H2S levels could have great potential therapeutic value. We report results of the design and evaluation of a class of N-mercapto (N-SH)-based H2S donors. Our results indicated that controllable H2S release from these donors could be achieved upon structural modifications. Selected donors (NSHD-1, NSHD-2, and NSHD-6) were tested in cellular models of oxidative damage showing significant cytoprotective effects. Moreover, NSHD-1 and NSHD-2 were also found to exhibit potent protective effects in a murine model of myocardial ischemia reperfusion (MI/R) injury. Furthermore, we report exciting findings of a cysteine based donor (XM-01) as an antiviral agent. Enveloped viruses cause devastating human and animal disease and are the most likely pathogens to cause global pandemics. Therefore, broad-spectrum antiviral compounds that target viral membranes are greatly sought after. The ideal antiviral would inhibit viral-cell membrane fusion and thus viral entry into host cells, combating infections by many enveloped viruses (e.g. Ebola, human immunodeficiency, influenza, and Nipah. We screened a library of sulfur-containing compounds and found several, including XM-01, which showed relatively high inhibitory properties against multiple pathogenic enveloped viruses, but no effect on the infection of a non-enveloped rotavirus. Moreover, our data indicated that XM-01 acts directly on the virus particles. Multidisciplinary approaches including membrane fluidity, cell-cell fusion, and electron microscopy assays showed that XM-01 compromised the viral membrane while leaving the envelope glycoproteins unaffected. Cells have membrane-repair mechanisms, explaining the low XM-01 cytotoxicity (CC50/EC50 ratio ~ 1000). Further, in contrast to other broad-spectrum viral membrane inhibitors like LJ001, XM-01’s inhibitory activity was not light-dependent, key to its potential uses. Notably, XM-0l has a lower likelihood of inducing viral resistance by mutagenesis of the viral genomes relative to other antivirals, as XM-01 targets the viral membrane. Thus, XM-01 and its derivatives have multiple desirable characteristics as sought-after broad-spectrum antiviral inhibitors of viral membranes and viral entry. Our findings prompt the pursuit of future derivatives, pharmacokinetics and in vivo effects, and further refinement of this new class of compounds’ mechanism and breadth of action.

SULFUR-CONTAINING COMPOUNDS AS HYDROGEN SULFIDE AND BROAD-SPECTRUM ANTIVIRAL AGENTS

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