In a recent study posted as an accepted manuscript in the journal Clinical infectious diseasesUniversity of Oklahoma researchers described three drugs with antiviral activity against monkeypox virus (MPXV).
Human monkeypox (hMPX) is a zoonosis caused by MPXV, a double-stranded (ds) DNA virus member of the genus Orthopoxvirus. The first case of hMPX was reported in the Democratic Republic of the Congo in 1970. There have been multiple outbreaks in West and Central Africa, with occasional outbreaks in North America and Europe.
Genomic research has revealed the existence of two clades of MPXV: the Congo Basin (CB) and West African (WA) clades. Managing MPXV infections has mainly been supportive care; however, antiviral drugs such as brincidofovir and tecovirimat have opened new therapeutic avenues.
By August 2, 2022, more than 25,000 confirmed cases of hMPX have been diagnosed in 83 countries. Preliminary evidence indicates that the WA clade is associated with the ongoing outbreak. Most cases have been reported in the United Kingdom (UK), Germany and Spain. In the current review, researchers described three antiviral drugs: brincidofovir (BCV), tecovirimat (ST-246) and cidofovir (CDV), which work against MPXV.
Study: Antivirals with activity against Monkeypox: a clinically oriented review. Image credit: NIAID
CDV is a prodrug and is phosphorylated to active CDV diphosphate (CDV-pp) after cell entry by host enzymes. The active drug is incorporated into the growing (viral) DNA strand during replication and slows down DNA synthesis. CDV resistance has also been characterized. CDV-resistant strains are less virulent than wild-type strains, implying that CDV resistance develops slowly at the expense of viral fitness.
Pharmacokinetic data suggest that the drug has poor oral absorption and is available as intravenous infusions. The efficacy of CDV has been evaluated in multiple animal models. Most studies assessed the use of CDV at the time of or shortly after viral exposure, and it remains unclear how findings in animals correlate with the timeline of human infection.
CDV has been used in humans to treat poxvirus infections. Case reports revealed the use of intravenous CDV in a multiple approach for ocular cowpox. The combined use with ST-246 has been documented in a patient with eczema vaccinatum. Topical CDV has been used in children and adults to treat molluscum contagiosum. Typically, lesions become acutely inflamed after CDV application, but disappear dramatically.
BCV, a lipid-conjugated analog of CDV, was approved in 2021 for the treatment of smallpox. BCV, like CDV, shows broad activity against dsDNA viruses. Unlike CDV, BCV readily enters host cells due to its lipophilic nature. BCV is hydrolyzed to CDV by phospholipases and phosphorylated to the active form (CDV-pp).
Higher levels of CDV-pp are noted after BCV administration, given the higher efficiency in crossing cell membranes. Cross-resistance to CDV and BCV is possible. Preliminary human studies reported absorption of oral BCV under fasting conditions, with lower peak plasma CDV levels. In addition, a higher penetration of BCV into the spleen, liver and lungs has been observed.
The prairie dog model for MPXV has a similar infection course as in humans. In these dogs, BCV improved survival when administered shortly after exposure to MPXV, indicating that early treatment is essential for efficacy.
ST-246 was approved in 2018 for the treatment of smallpox. The drug works against orthopox viruses, but not against other dsDNA viruses. ST-246 targets the gene encoding p37, a conserved membrane protein involved in the formation of the extracellular enveloped virus. ST-246 does not inhibit protein/DNA synthesis or formation of the mature virus.
Drug resistance could arise from a single amino acid change, although it is unknown whether this genetic change in p37 results in an adverse fitness for orthopoxviruses. ST-246 showed activity against vaccinia virus strains resistant to CDV; furthermore, there is no evidence of cross-resistance to ST-246 and CDV/BCV.
ST-246 is available in oral and intravenous formulations. It has superior absorption when administered in a fed state. It has been effective against MPXV in macaques and prairie dogs. Administration of ST-246 within 72 hours of poxvirus exposure was effective in reducing lesion severity and preventing mortality in several animal models.
Co-administration of ST-246 and BCV results in synergistic activity. For example, in cowpox-infected mice, the combination therapy was associated with lower mortality compared to treatment with individual drugs. ST-246 has been used to treat orthopoxviruses in selected humans, including in two cases for treatment with MPXV.
In one patient, the oral course was started five days after the onset of the rash for two weeks. The patient made a full recovery without complications and was discharged. Detailed information about the other patient is limited, except for the full recovery.
In summary, CDV, BCV and ST-246 exhibit activity against MPXV. CDV and BCV inhibit DNA replication and exhibit broad activity against various dsDNA viruses. In contrast, ST-246 is much more specific for orthopoxviruses and prevents the formation of the enveloped virus, which is essential for cell-to-cell transmission.
Overall, ST-246 and BCV could be promising therapeutic candidates based on their tolerability profiles. Further studies are needed to identify those at higher risk for MPXV and associated complications and to determine the optimal starting time and duration of therapy.