Drug Sensitivity of Currently Circulating Mpox Viruses

Bojkova, Denisa; Bechtel, Marco; Rothenburger, Tamara; Steinhorst, Katja; Zöller, Nadja; Kippenberger, Stefan; Schneider, Julia; Corman, Victor M.; Uri, Hannah; Wass, Mark N.; Knecht, Gaby; Khaykin, Pavel; Wolf, Timo; Ciesek, Sandra; Rabenau, Holger F.; Michaelis, Martin; Cinatl, Jindrich

doi:10.1056/nejmc2212136

Cited by 19 publications

(23 citation statements)

References 5 publications

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“…Tecovirimat (F13L inhibitor) and brincidofovir (DNA polymerase inhibitor) are the antiviral drugs that are currently mainly considered for mpox treatment. 2,3,15 There are concerns about the potential emergence of tecovirimat-resistant mpox virus strains, 2 and the formation of a tecovirimat-resistant vaccinia virus was described in an immunocompromised acute myeloid leukaemia patient after inoculation with the vaccinia virus-based ACAM2000 smallpox vaccine. 48 We established a tecovirimat-resistant mpox virus strain (MPXV1 r TECO), which harboured the known tecovirimat resistance mutations N267D and I372N, by adapting MPXV1 to tecovirimat in a one round selection step using a high tecovirimat concentration (4 µM).…”

Section: Discussionmentioning

confidence: 99%

“…Mpox virus was cultured in primary human foreskin fibroblasts (HFF) and primary human foreskin keratinocytes (HFK) as previously described. 15 When added to the culture medium together with the virus, nitroxoline inhibited mpox virus infection in HFF and HFK in a dosedependent manner (Figure 1B 1). Nitroxoline did not affect cell viability in the tested concentration range of up to 20 µM (Figure 1C,D).…”

Section: Effects Of Nitroxoline On Mpox Virus Replicationmentioning

confidence: 92%

“…E353K is shared between isolates from the current global outbreak and was shown not to affect tecovirimat efficacy. 15 In contrast, N267D and I372N were previously shown to provide resistance to tecovirimat and are, hence, likely responsible for the observed tecovirimat resistance. 41,42 Notably, MPXV1 r TECO remained sensitive to both brincidofovir and nitroxoline (Figure 4B).…”

Section: Nitroxoline Inhibits a Tecovirimat-resistant Mpox Virus Strainmentioning

confidence: 97%

“…Three antiviral drugs (tecovirimat [ST‐246], brincidofovir [CMX001], cidofovir) are mainly considered for mpox treatment, although they have not undergone clinical testing for mpox treatment 1–5 . Despite differences in the clinical presentation of the current mpox outbreak compared to previous ones, 2,3,8,13,14 recent findings indicated that these three drugs are still effective against the currently circulating mpox viruses in therapeutically achievable concentrations 15–17 …”

Section: Introductionmentioning

confidence: 99%

“…[1][2][3][4][5] Despite differences in the clinical presentation of the current mpox outbreak compared to previous ones, 2,3,8,13,14 recent findings indicated that these three drugs are still effective against the currently circulating mpox viruses in therapeutically achievable concentrations. [15][16][17] Notably, the use of cidofovir and brincidofovir is associated with severe, therapy-limiting side effects. 2,18 Moreover, the availability of tecovirimat is limited and may be affected by resistance formation.…”

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confidence: 99%

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Repurposing of the antibiotic nitroxoline for the treatment of mpox

Bojkova

Zöller

Tietgen

et al. 2023

Journal of Medical Virology

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The antiviral drugs tecovirimat, brincidofovir, and cidofovir are considered for mpox (monkeypox) treatment despite a lack of clinical evidence. Moreover, their use is affected by toxic side‐effects (brincidofovir, cidofovir), limited availability (tecovirimat), and potentially by resistance formation. Hence, additional, readily available drugs are needed. Here, therapeutic concentrations of nitroxoline, a hydroxyquinoline antibiotic with a favourable safety profile in humans, inhibited the replication of 12 mpox virus isolates from the current outbreak in primary cultures of human keratinocytes and fibroblasts and a skin explant model by interference with host cell signalling. Tecovirimat, but not nitroxoline, treatment resulted in rapid resistance development. Nitroxoline remained effective against the tecovirimat‐resistant strain and increased the anti‐mpox virus activity of tecovirimat and brincidofovir. Moreover, nitroxoline inhibited bacterial and viral pathogens that are often co‐transmitted with mpox. In conclusion, nitroxoline is a repurposing candidate for the treatment of mpox due to both antiviral and antimicrobial activity.

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Section: Discussionmentioning

confidence: 99%

Section: Effects Of Nitroxoline On Mpox Virus Replicationmentioning

confidence: 92%

Section: Nitroxoline Inhibits a Tecovirimat-resistant Mpox Virus Strainmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Repurposing of the antibiotic nitroxoline for the treatment of mpox

Bojkova

Zöller

Tietgen

et al. 2023

Journal of Medical Virology

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

Cinatl,

Bechtel,

Reus

et al. 2024

Journal of Medical Virology

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The Mpox virus can cause severe disease in the susceptible population with dermatologic and systemic manifestations. Furthermore, ophthalmic manifestations of mpox infection are well documented. Topical trifluridine (TFT) eye drops have been used for therapy of ophthalmic mpox infection in patients, however, its efficacy against mpox virus infection in this scenario has not been previously shown. In the present study, we have established ophthalmic cell models suitable for the infection with mpox virus. We show, that TFT is effective against a broad range of mpox isolates in conjunctival epithelial cells and keratocytes. Further, TFT remained effective against a tecovirimat‐resistant virus strain. In the context of drug combinations, a nearly additive effect was observed for TFT combinations with brincidofovir and tecovirimat in conjunctival epithelial cells, while a slight antagonism was observed for both combinations in keratocytes. Altogether, our findings demonstrate TFT as a promising drug for treatment of ophthalmic mpox infection able to overcome tecovirimat resistance. However, conflicting results regarding the effect of drug combinations with approved compounds warrant close monitoring of such use in patients.

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A clinically used anti‐human papilloma virus agent (3‐hydroxyphthalic anhydride‐modified bovine β‐lactoglobulin) has a potential for topical application to prevent sexual transmission of monkeypox virus

Sha,

Huang,

Hua

et al. 2024

MedComm

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A global outbreak of monkeypox (mpox) caused by the mpox virus (MPXV) has posed a serious threat to public health worldwide, thus calling for the urgent development of antivirals and vaccines to curb its further spread. In this study, we screened 41 anhydride‐modified proteins and found that 3‐hydroxyphthalic anhydride‐modified β‐lactoglobulin (3HP‐β‐LG), a clinically used anti‐HPV agent, was highly effective in inhibiting infection of vaccinia virus Tiantan strain (VACV‐VTT) and MPXV. Mechanistic studies demonstrated that 3HP‐β‐LG bound to the virus, not the host cell, by targeting the early stage of virus entry, possibly through the interaction between the amino acids with negatively charges in 3HP‐β‐LG and the key amino acids with positive charges in the target region of A29L, a key surface protein of MPXV. A synergistic effect was observed when 3HP‐β‐LG was combined with tecovirimat, a small‐molecule antiviral drug approved by the United States Food and Drug Administration and the European Medicine Agency for the treatment of smallpox and mpox. Because of its clinically proven safety and stability, 3HP‐β‐LG shows promise for further development as a prophylactic agent to prevent the sexual transmission of MPXV.

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Drug Sensitivity of Currently Circulating Mpox Viruses

Cited by 19 publications

References 5 publications

Repurposing of the antibiotic nitroxoline for the treatment of mpox

Repurposing of the antibiotic nitroxoline for the treatment of mpox

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

A clinically used anti‐human papilloma virus agent (3‐hydroxyphthalic anhydride‐modified bovine β‐lactoglobulin) has a potential for topical application to prevent sexual transmission of monkeypox virus

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