Drug Development against Smallpox: Present and Future

Abstract

Forty years after the last endemic smallpox case, variola virus (VARV) is still considered a major threat to humans due to its possible use as a bioterrorism agent. For many years, the risk of disease reemergence was thought to solely be through deliberate misuse of VARV strains kept in clandestine laboratories. However, recent experiments using synthetic biology have proven the feasibility of recreating a poxvirus de novo, implying that VARV could, in theory, be resurrected. Because of this new perspective, the WHO Advisory Committee on VARV Research released new recommendations concerning research on poxviruses that strongly encourages pursuing the development of new antiviral drugs against orthopoxviruses. In 2018, the U.S. FDA advised in favor of two molecules for smallpox treatment, tecovirimat and brincidofovir. This review highlights the difficulties to develop new drugs targeting an eradicated disease, especially as it requires working under the FDA “animal efficacy rule” with the few, and imperfect, animal models available.

Identification of Vaccinia Virus Inhibitors and Cellular Functions Necessary for Efficient Viral Replication by Screening Bioactives and FDA-Approved Drugs

“…Moreover, the continued surveillance and discovery of novel therapeutics for poxvirus infections are important for preventing emerging and re-emerging poxvirus pathogens other than VARV. In fact, the U.S. federal government is actively seeking additional drugs to treat smallpox and other poxvirus diseases [ 15 , 17 , 18 ]. In the past two decades, several antivirals for poxviruses have been identified, including CMX001, Tecovirimat, and CMLDBU6128 [ 17 ].…”

“…In fact, the U.S. federal government is actively seeking additional drugs to treat smallpox and other poxvirus diseases [ 15 , 17 , 18 ]. In the past two decades, several antivirals for poxviruses have been identified, including CMX001, Tecovirimat, and CMLDBU6128 [ 17 ]. However, mutant viruses resistant to these drugs have also been identified, strongly incentivizing the identification of other new antivirals for poxvirus infections [ 17 , 18 ].…”

“…In the past two decades, several antivirals for poxviruses have been identified, including CMX001, Tecovirimat, and CMLDBU6128 [ 17 ]. However, mutant viruses resistant to these drugs have also been identified, strongly incentivizing the identification of other new antivirals for poxvirus infections [ 17 , 18 ]. In addition to identifying drugs targeting viral components, an alternative approach is to discover compounds that target cellular functions required for efficient viral replication.…”

Pharmacokinetics and Efficacy of a Potential Smallpox Therapeutic, Brincidofovir, in a Lethal Monkeypox Virus Animal Model

“…As advances in synthetic biology allow for manipulation or recreation of viruses, it is important to remain vigilant in identifying sufficient therapeutic options should an outbreak occur. Current considerations for preparedness response in the event of a smallpox outbreak have suggested the need for two antiviral compounds with separate mechanisms of action to be licensed and ready for use (11). To date, a small-molecule compound, TPOXX (ST-246 or tecovirimat), has recently gained FDA licensure for use against smallpox and remains the only FDA-approved antipoxviral drug (12).…”

Antiviral Classification

“…As an 4-trifluoromethyl phenol derivative, tecovirimat blocks the interactions of VP37 with Rab8 and TIP47, thereby inhibiting the maturation of egress-competent enveloped virions for viral budding ( Jordan et al ., 2010 ). Novel compounds such as NIOCH-14 are still under development ( Delaune and Iseni, 2020 ).…”