The Microtubule Inhibitor Podofilox Inhibits an Early Entry Step of Human Cytomegalovirus

Abstract

Human cytomegalovirus is a ubiquitous β-herpesvirus that infects many different cell types through an initial binding to cell surface receptors followed by a fusion event at the cell membrane or endocytic vesicle. A recent high-throughput screen to identify compounds that block a step prior to viral gene expression identified podofilox as a potent and nontoxic inhibitor. Time-of-addition studies in combination with quantitative-PCR analysis demonstrated that podofilox limits an early step of virus entry at the cell surface. Podofilox was also able to drastically reduce infection by herpes simplex 1, an α-herpesvirus with a very similar entry process to CMV. Podofilox caused a reduced maximal plateau inhibition of infection by viruses with single step binding processes prior to fusion-like Newcastle disease virus, Sendai virus, and influenza A virus or viruses that enter via endocytosis like vesicular stomatitis virus and a clinical-like strain of CMV. These results indicate that microtubules appear to be participating in the post-binding step of virus entry including the pre- and post-penetration events. Modulation of the plasma membrane is required to promote virus entry for herpesviruses, and that podofilox, unlike colchicine or nocodazole, is able to preferentially target microtubule networks at the plasma membrane.

Molecular profiling of individual FDA-approved clinical drugs identifies modulators of nonsense-mediated mRNA decay

“… 56 , 57 , 58 Vindesine sulfate, podofilox, albendazole, and vinorelbine tartrate are microtubule modulators. 59 , 60 , 61 We also listed the top 15 ranked drugs that decreased the N_Ptbp2 / F_Ptbp2 , N_Hnrnpl / F_Hnrnpl , and N_Tra2b / F_Tra2b ratio ( Figures 4 D–4F). Annotations of these drugs from PubChem indicate a wide range of actions from cellular enzyme inhibitors (bestatin, naproxen sodium, pyridostigmine bromide, and pravastatin sodium), 62 , 63 , 64 , 65 inflammatory response regulators (triamcinolone acetonide, naproxen sodium, cortisone acetate, and diflunisal), 66 , 67 , 68 , 69 to antibiotic reagents (sulfacetamide, cefixime trihydrate, mafenide acetate, and ampicillin sodium).…”

Effect of Clinically Used Microtubule Targeting Drugs on Viral Infection and Transport Function

“…In contrast, NOC or MBZ binding to zones 2 and 3 do not involve alterations on the conformation of these loops. Also, their effect varies depending on the cellular area and, for instance, PPT preferably targets MT at the plasma membrane rather than those filaments closer to the nucleus [ 66 ]. Moreover, it has been found that NOC does not have a significant effect on MTs built from acetylated α-tubulin of certain cell types [ 58 , 67 ].…”

Entry of the Varicellovirus Canid herpesvirus 1 into Madin–Darby canine kidney epithelial cells is pH ‐independent and occurs via a macropinocytosis‐like mechanism but without increase in fluid uptake

“…Paradoxically, podofilox, a microtubule polymerisation inhibitor, has been found to block CMV entry. It has been proposed that this drug may have a different impact on the more dynamic microtubules at the cell surface compared to the more stable intracellular microtubules (Cohen et al, 2016). It remains to be determined whether the sensitivity of HCMV entry to podofilox reflect a mechanistic difference in the macropinocytic‐like entry pathways of CHV‐1 and HCMV.…”