Identification of inosine monophosphate dehydrogenase as a potential target for anti-monkeypox virus agents

Abstract

Monkeypox virus (MPXV) is a neglected zoonotic pathogen that caused a worldwide outbreak in May 2022. Given the lack of an established therapy, the development of an anti-MPXV strategy is of vital importance. To identify drug targets for the development of anti-MPXV agents, we screened a chemical library using an MPXV infection cell assay and found that gemcitabine, trifluridine, and mycophenolic acid (MPA) inhibited MPXV propagation. These compounds showed broad-spectrum anti-orthopoxvirus activities and presented lower 90% inhibitory concentrations (0.032-1.40 microM) than brincidofovir, an approved anti-smallpox agent. These three compounds have been suggested to target the post-entry step to reduce the intracellular production of virions. Knockdown of inosine monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme of guanosine biosynthesis and a target of MPA, dramatically reduced MPXV DNA production. Moreover, supplementation with guanosine recovered the anti-MPXV effect of MPA, suggesting that IMPDH and its guanosine biosynthetic pathway regulate MPXV replication. By targeting IMPDH, we identified a series of compounds with stronger anti-MPXV activity than MPA. These evidences propose that IMPDH is a potential target for the development of anti-MPXV agents.

Trifluridine for treatment of mpox infection in drug combinations in ophthalmic cell models

“…However, an intercell type variation in efficacy of TFT could be observed (Figure 1C). In DF, TFT inhibited mpox virus with IC 50 values comparable to previously described TFT efficacy in Vero cells 10 as well as against other orthopoxviruses. 11 In contrast, TFT displayed twofold lower potency in keratocytes (mean IC 50 values 1.11 µM) and HConEpiC (mean IC 50 values 0.95 µM) in comparison to DF (mean IC 50 values 0.42 µM).…”

“…2 A recent in vitro study demonstrated the antiviral efficacy of TFT against mpox infection in Vero cells. 10 However, the efficacy of antiviral drugs may differ between laboratory cell lines and primary cells derived from relevant tissues. 17,18 Here, we show that TFT inhibits infection of a broad range of mpox isolates in cell models relevant for ophthalmic manifestations, albeit with lower efficacy than in dermal cells.…”

“…TFT is a nucleoside analog, which has been approved for other ophthalmic conditions like herpes simplex keratitis 2 . A recent in vitro study demonstrated the antiviral efficacy of TFT against mpox infection in Vero cells 10 . However, the efficacy of antiviral drugs may differ between laboratory cell lines and primary cells derived from relevant tissues 17,18 .…”

Unlocking the Secret Vault of Promising Drug Targets from Mpox Proteome- A Computational Approach

“…Experimental validation of the identified drug targets and their binding sites is crucial for confirming the feasibility of these targets as potential candidates for drug development. In addition to the drug targets discussed in this study, two other notable mentions are IMPDH (Inosine-5′-monophosphate dehydrogenase) 134 and G-quadruplexes 135 . Through its regulation of the guanine nucleotide biosynthesis In conclusion, we have identified 33 putative therapeutic targets within the Mpox proteome (strain Zaire-96-I-16) through extensive literature surveys and structural studies.…”

“…MPXV DNA production is drastically reduced upon the knockdown of IMPDH, the rate-limiting enzyme in guanosine biosynthesis. It has been demonstrated that mycophenolic acid (MPA) targets IMPDH and efficiently prevents the spread of Mpox134 . G-quadruplex (GQ) secondary structures are becoming more and more important in antiviral tactics.…”