Author: Ahmed, S. Kaleem ; Smith, Jessica L. ; Sulgey, Gauthami ; Karyakarte, Shuklendu ; Suto, Mark J. ; Hirsch, Alec J. ; Streblow, Daniel N. ; Augelli-Szafran, Corinne E. ; Ahmad, Fahim ; Haese, Nicole N. ; Rasmussen, Lynn ; Zhang, Sixue ; Medica, Samuel ; DeFilippis, Victor ; Moukha-Chafiq, Omar ; Bostwick, Robert ; Tekwani, Babu ; Heise, Mark T. ; Pathak, Ashish K. ; Garzan, Atefeh ; Morrison, Thomas E.

2-(Methylthio)-N-(4-(naphthalen-2-yl)thiazol-2-yl)nicotinamide 1 was identified as an inhibitor against Chikungunya virus (CHIKV) with good antiviral activity [EC₅₀ = 0.6 μM; EC₉₀ = 0.93 μM and viral titer reduction (VTR) of 6.9 logs at 10 μM concentration] with no observed cytotoxicity (CC₅₀ = 132 μM) in normal human dermal fibroblast (NHDF) cells. Structure-activity relationship (SAR) studies to further improve the potency, efficacy, and drug-like properties of 1 led to the discovery of a new potent inhibitor N-(4-(3-((4-cyanophenyl)amino)phenyl)thiazol-2-yl)-2-(methylthio)nicotinamide 26, which showed a VTR of 8.7 logs at 10 μM against CHIKV and an EC₉₀ of 0.45 μM with considerably improved MLM stability (t_1/2 = 74 min) as compared to 1. Mechanism of action studies show that 26 inhibits alphavirus replication by blocking subgenomic viral RNA translation and structural protein synthesis. The in vivo efficacy studies of compound 26 on CHIKV infection in mice are reported.

08 Oct 2024·Antimicrobial Agents and Chemotherapy

Design of novel and highly selective SARS-CoV-2 main protease inhibitors

Article

Author: Register, Emery T. ; Keeney, Frederick ; Poli, Adi N. R. ; Rajaiah, Rajesh ; Pandey, Kabita ; Verma, Atul K. ; Byrareddy, Siddappa N. ; Acharya, Arpan ; Tietjen, Ian ; Montaner, Luis J. ; Salvino, Joseph M. ; Cassel, Joel ; Nandwana, Nitesh K. ; Messick, Troy E.

ABSTRACT We have synthesized a novel and highly selective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease peptide mimetic inhibitor mimicking the replicase 1ab recognition sequence -Val-Leu-Gln- and utilizing a cysteine selective acyloxymethyl ketone as the electrophilic warhead to target the active site Cys145. Utilizing a constrained cyclic peptide that locks the conformation between the P3 (Val) and P2 (Leu) residues, we identified a highly selective inhibitor that fills the P2 pocket occupied by the leucine residue sidechain of PF-00835231 and the dimethyl-3-azabicyclo-hexane motif in nirmatrelvir (PF-07321332). This strategy resulted in potent and highly selective Mpro inhibitors without inhibiting essential host cathepsin cysteine or serine proteases. The lead prototype compound 1 (MPro IC 50 = 230 ± 18 nM) also inhibits the replication of multiple SARS-CoV-2 variants in vitro , including SARS-CoV-2 variants of concern, and can synergize at lower concentrations with the viral RNA polymerase inhibitor, remdesivir, to inhibit replication. It also reduces SARS-CoV-2 replication in SARS-CoV-2 Omicron-infected Syrian golden hamsters without obvious toxicities, demonstrating in vivo efficacy. This novel lead structure provides the basis for optimization of improved agents targeting evolving SARS-CoV-2 drug resistance that can selectively act on Mpro versus host proteases and are less likely to have off-target effects due to non-specific targeting. Developing inhibitors against the active site of the main protease (Mpro), which is highly conserved across coronaviruses, is expected to impart a higher genetic barrier to evolving SARS-CoV-2 drug resistance. Drugs that selectively inhibit the viral Mpro are less likely to have off-target effects warranting efforts to improve this therapy.

01 Aug 2024·Recent Advances in Anti-Infective Drug Discovery

Outpatient Intravenous Remdesivir to Prevent Progression to Severe COVID-19: An Observational Study from a Greek Hospital

Article

Author: Galinos, Iosif ; Kintrilis, Nikolaos

Background:Remdesivir, a viral RNA polymerase inhibitor, has been a powerful weapon in the battle against the SARS-CoV-2 pandemic. Originally approved for use in hospitalized patients, remdesivir improves clinical outcomes in patients with moderate to severe coronavirus disease 2019 (COVID-19). After proving efficacious in hospitalized patients, its use was approved in early disease for symptomatic, non-hospitalized patients that present risk factors for progression to severe disease.Objective:To evaluate whether administration of the antiviral medication remdesivir at an outpatient basis has an effect on hospital admissions of patients presenting with SARSCoV- 2 infection.Methods:We conducted an observational clinical trial involving 107 non-hospitalized COVID-19 patients who attended the emergency department of a third-level greek hospital seeking care for symptoms appearing within the previous 5 days and who had at least one risk factor for progression to severe disease. After arterial blood gas evaluation, eligible patients received intravenous remdesivir at a dose of 200 mg on day 1 and 100 mg on days 2 and 3. The efficacy endpoint was set as COVID-19-related hospitalization or death in the next 14 days.Results:A total of 107 patients (57.0% men) participated in the study, 51 (47.7%) of them fully vaccinated. Most prevalent were age ≥ 60 years old, cardiovascular/cerebrovascular disease, immunosuppression or malignancy, obesity, diabetes mellitus, and chronic lung disease. All patients enrolled completed the 3-day course, with a total of 3 out of 107 patients (2.8%) eventually having a COVID-19-related hospitalization by day 14, while no deaths were reported by day 14.Conclusion:Among non-hospitalized patients with at least one risk factor for progression to severe COVID-19, a 3-day course of intravenous remdesivir yielded favourable results.

100 Deals associated with Viral RNA inhibitors(Southern Research Institute)

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Indication	Highest Phase	Country/Location	Organization	Date
Chikungunya Fever	Preclinical	United States	Southern Research Institute	02 Dec 2024

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