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

Smallpox, caused by Variola virus (VARV), was eradicated in 1980; however, VARV bioterrorist threats still exist, necessitating readily available therapeutics. Current preparedness activities recognize the importance of oral antivirals and recommend therapeutics with different mechanisms of action. Monkeypox virus (MPXV) is closely related to VARV, causing a highly similar clinical human disease, and can be used as a surrogate for smallpox antiviral testing. The prairie dog MPXV model has been characterized and used to study the efficacy of antipoxvirus therapeutics, including recently approved TPOXX (tecovirimat). Brincidofovir (BCV; CMX001) has shown antiviral activity against double-stranded DNA viruses, including poxviruses. To determine the exposure of BCV following oral administration to prairie dogs, a pharmacokinetics (PK) study was performed. Analysis of BCV plasma concentrations indicated variability, conceivably due to the outbred nature of the animals. To determine BCV efficacy in the MPXV prairie dog model, groups of animals were intranasally challenged with 9 × 105 plaque-forming units (PFU; 90% lethal dose [LD90]) of MPXV on inoculation day 0 (ID0). Animals were divided into groups based on the first day of BCV treatment relative to inoculation day (ID-1, ID0, or ID1). A trend in efficacy was noted dependent upon treatment initiation (57% on ID-1, 43% on ID0, and 29% on ID1) but was lower than demonstrated in other animal models. Analysis of the PK data indicated that BCV plasma exposure (maximum concentration [Cmax]) and the time of the last quantifiable concentration (AUClast) were lower than in other animal models administered the same doses, indicating that suboptimal BCV exposure may explain the lower protective effect on survival.IMPORTANCE Preparedness activities against highly transmissible viruses with high mortality rates have been highlighted during the ongoing coronavirus disease 2019 (COVID-19) pandemic. Smallpox, caused by variola virus (VARV) infection, is highly transmissible, with an estimated 30% mortality. Through an intensive vaccination campaign, smallpox was declared eradicated in 1980, and routine smallpox vaccination of individuals ceased. Today's current population has little/no immunity against VARV. If smallpox were to reemerge, the worldwide results would be devastating. Recent FDA approval of one smallpox antiviral (tecovirimat) was a successful step in biothreat preparedness; however, orthopoxviruses can become resistant to treatment, suggesting the need for multiple therapeutics. Our paper details the efficacy of the investigational smallpox drug brincidofovir in a monkeypox virus (MPXV) animal model. Since brincidofovir has not been tested in vivo against smallpox, studies with the related virus MPXV are critical in understanding whether it would be protective in the event of a smallpox outbreak.

Drug designing against NSP15 of SARS-COV2 via high throughput computational screening and structural dynamics approach.

The rapid outbreak of the COVID-19 also known as SARS-CoV2 has been declared pandemic with serious global concern. As there is no effective therapeutic against COVID-19, there is an urgent need for explicit treatment against it. The focused objective of the current study is to propose promising drug candidates against the newly identified potential therapeutic target (endonuclease, NSP15) of SARS-CoV2. NSP15 is an attractive druggable target due to its critical role in SARS-CoV2 replication and virulence in addition to interference with the host immune system. Here in the present study, we integrated the high throughput computational screening and dynamic simulation approach to identify the most promising candidate lead compound against NSP15.5-fluoro-2-oxo-1H-pyrazine-3-carboxamide (favipiravir), (3R,4R, 5R)-3,4-Bis(benzyloxy)-5-((benzyloxy) methyl) dihydrofuran-2(3H)-one) remedesivir, 1,3-thiazol-5-ylmethyl N-[(2S,3S, 5S)-3-hydroxy-5-[[(2 S)-3-methyl-2-[[methyl-[(2-propan-2-yl-1,3-thiazol-4-yl)methyl]carbamoyl]amino]butanoyl]amino]-1,6-diphenylhexan-2-yl]carbamate (ritonavir), ethyl (3R,4R, 5S)-4-acetamido-5-amino-3-pentan-3-yloxycyclohexene-1-carboxylate (oseltamivir), and (2 S)-N-[(2S,4S, 5S)-5-[[2-(2,6-dimethylphenoxy)acetyl]amino]-4-hydroxy-1,6-diphenylhexan-2-yl]-3-methyl-2-(2-oxo-1,3-diazinan-1-yl)butanamide (lopinavir) were chosen as a training set to generate the pharmacophore model. A dataset of ~140,000 compounds library was screened against the designed pharmacophore model and 10 unique compounds were selected that passed successfully through geometry constraints, Lipinski Rule of 5, and ADME/Tox filters along with a strong binding affinity for NSP15 binding cavity. The best fit compound was selected for dynamic simulation to have detailed structural features critical for binding with the NSP15 protein. Given our detailed integrative computational analysis, a Small molecule (3,3-Dimethyl-N-[4-(1-piperidinylcarbonyl) phenyl] butanamide) with drug-like properties and high binding affinity with the NSP15 is proposed as a most promising potential drug against COVID-19. The current computational integrative approach may complement high-throughput screening and the shortlisted small molecule may contribute to selective targeting of NSP15 to stop the replication of SARS-CoV2.