The new small molecule non-nucleoside inhibitor was effective in both in vitro and in vivo studies although no testing against HHV-6 was reported.
Immunocompromised patients at risk for herpesvirus disease are often given prophylactic treatment with high-dose nucleos(t)ide analogue drugs that target a shared, conserved DNA polymerase. These drugs typically target the viral DNA polymerase, with the treatment regimens being specific to particular herpesviruses. The treatments can produce nephrotoxicity and other adverse drug events, and can generate drug-resistant variants.
Merck reports that it has developed a new class of broad-spectrum anti-herpesvirus agents: an oxazolidinone class of broad-spectrum non-nucleoside inhibitors. The drugs have potent biochemical and broad-spectrum cellular activity, and were effective in murine models against both HSV-1 and CMV infection.
Using high throughput screening (HTS) of a library of over 100,000 compounds, and using in silico predictive methods to modify compounds to increase efficacy and reduce toxicity, the Merck team identified a molecule it calls compound 42. This molecule was found to be effective for CMV and VZV inhibition, in vitro.
The team then proceeded to conduct in vivo studies in mice to assess the effectiveness of compound 42 for both treatment and for prophylaxis. The in vivo efficacy against HSV-1 was performed with an intranasal challenge that has been shown to predict efficacy against Herpes encephalitis. Five groups of mice were treated with either: compound 42 BID at a 30 mg/kg dose; compound 42 BID at a 150 mg/kg dose; acyclovir (ACV) dosed BID at 30 and 120 mg/kg doses, as a positive control; or vehicle only. Mice were treated for 7 days at doses predicted to target the EC90 and EC50 at trough. The results are shown in Figure 1, below:
Figure 1. Survival of therapeutically treated mice post HSV-1 nasal challenge. The higher dose of compound (42) was most effective.
On day four, half the mice from each group were sacrificed and evaluated for viral load in lung and brain. As shown in Figure 2, the highest dose of compound 42 achieved the lowest viral DNA load in the brain.
Figure 2. Viral DNA load in the brain in therapeutically treated mice post HSV-1 nasal challenge. The higher dose of compound 42 was most effective.
To assess the prophylactic efficacy of compound 41, four groups were treated BID prophylactically 2 days prior to infection with: compound 42 BID at a 30 mg/kg dose; compound 42 BID at a 150 mg/kg dose; acyclovir (ACV) dosed BID at a 120 mg/kg dose, as a positive control; or vehicle only. A fifth group of mice was treated well after nasal challenge (Post). As shown in Figure 3, below, the highest dose of compound 42 was most effective in achieving survival.
Figure 3. Survival of prophylactically treated mice post HSV-1 nasal challenge. The higher dose of compound (2 was most effective.
Having assessed the efficacy of compound 42 against HSV-1 in mice, efficacy against murine CMV then was tested. The investigators assessed the prophylactic effectiveness of compound 42 at reducing viral load in mice with murine CMV following an intraperitoneal challenge. Compound 42 at a 30 mg/kg dose and at a 150 mg/kg dose was compared to ganciclovir (GCV) given both intraperitoneally and orally. Compound 42 at the highest dose led to the lowest viral load in spleen, as shown in Figure 4, below.
Figure 4. Viral DNA load in spleen in mice treated prophylactically either with ganciclovir (GCV) intraperitoneally (IP) or orally (PO), or with compound (42) at two doses.
In summary, investigators from Merck have reported the discovery of a novel series of non-nucleoside inhibitors of herpes DNA polymerase, and shown that—in mice—it has in vitro and in vivo effectiveness against both HSV-1 in mice (for treatment and prophylaxis), and murine CMV (for prophylaxis). The effectiveness of compound 42 for treatment against murine CMV, and for treatment and prophylaxis against other human herpesviruses, including HHV-6A/B, remains to be tested. However, the development of a new class of antivirals against herpesviruses is an encouraging development.
Read the full article: Plotkin 2024