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ACS Infect Dis ; 8(6): 1147-1160, 2022 06 10.
Article in English | MEDLINE | ID: covidwho-1860283


There are currently relatively few small-molecule antiviral drugs that are either approved or emergency-approved for use against severe acute respiratory coronavirus 2 (SARS-CoV-2). One of these is remdesivir, which was originally repurposed from its use against Ebola. We evaluated three molecules we had previously identified computationally with antiviral activity against Ebola and Marburg and identified pyronaridine, which inhibited the SARS-CoV-2 replication in A549-ACE2 cells. The in vivo efficacy of pyronaridine has now been assessed in a K18-hACE transgenic mouse model of COVID-19. Pyronaridine treatment demonstrated a statistically significant reduction of viral load in the lungs of SARS-CoV-2-infected mice, reducing lung pathology, which was also associated with significant reduction in the levels of pro-inflammatory cytokines/chemokine and cell infiltration. Pyronaridine inhibited the viral PLpro activity in vitro (IC50 of 1.8 µM) without any effect on Mpro, indicating a possible molecular mechanism involved in its ability to inhibit SARS-CoV-2 replication. We have also generated several pyronaridine analogs to assist in understanding the structure activity relationship for PLpro inhibition. Our results indicate that pyronaridine is a potential therapeutic candidate for COVID-19.

COVID-19 , Hemorrhagic Fever, Ebola , Animals , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Hemorrhagic Fever, Ebola/drug therapy , Mice , Naphthyridines , SARS-CoV-2
Eur J Med Chem ; 211: 113014, 2021 Feb 05.
Article in English | MEDLINE | ID: covidwho-918799


Viruses are obligate intracellular parasites and have evolved to enter the host cell. To gain access they come into contact with the host cell through an initial adhesion, and some viruses from different genus may use heparan sulfate proteoglycans for it. The successful inhibition of this early event of the infection by synthetic molecules has always been an attractive target for medicinal chemists. Numerous reports have yielded insights into the function of compounds based on the dispirotripiperazine scaffold. Analysis suggests that this is a structural requirement for inhibiting the interactions between viruses and cell-surface heparan sulfate proteoglycans, thus preventing virus entry and replication. This review summarizes our current knowledge about the early history of development, synthesis, structure-activity relationships and antiviral evaluation of dispirotripiperazine-based compounds and where they are going in the future.

Antiviral Agents/pharmacology , Drug Design , Piperazines/pharmacology , Spiro Compounds/pharmacology , Viruses/drug effects , Antiviral Agents/chemistry , Heparan Sulfate Proteoglycans/antagonists & inhibitors , Heparan Sulfate Proteoglycans/metabolism , Molecular Structure , Piperazines/chemistry , Spiro Compounds/chemistry , Viruses/metabolism
Pathog Dis ; 78(7)2020 10 07.
Article in English | MEDLINE | ID: covidwho-733382


Influenza virus and coronaviruses continue to cause pandemics across the globe. We now have a greater understanding of their functions. Unfortunately, the number of drugs in our armory to defend us against them is inadequate. This may require us to think about what mechanisms to address. Here, we review the biological properties of these viruses, their genetic evolution and antiviral therapies that can be used or have been attempted. We will describe several classes of drugs such as serine protease inhibitors, heparin, heparan sulfate receptor inhibitors, chelating agents, immunomodulators and many others. We also briefly describe some of the drug repurposing efforts that have taken place in an effort to rapidly identify molecules to treat patients with COVID-19. While we put a heavy emphasis on the past and present efforts, we also provide some thoughts about what we need to do to prepare for respiratory viral threats in the future.

Antiviral Agents/therapeutic use , Coronavirus Infections/epidemiology , Coronavirus/drug effects , Drug Repositioning , Influenza, Human/epidemiology , Orthomyxoviridae/drug effects , Pandemics , Anticoagulants/therapeutic use , Antimalarials/therapeutic use , Antioxidants/therapeutic use , Chelating Agents/therapeutic use , Coronavirus/genetics , Coronavirus/growth & development , Coronavirus/pathogenicity , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Glycoconjugates/therapeutic use , Humans , Immunologic Factors/therapeutic use , Influenza, Human/drug therapy , Influenza, Human/virology , Orthomyxoviridae/genetics , Orthomyxoviridae/growth & development , Orthomyxoviridae/pathogenicity , Serine Proteinase Inhibitors/therapeutic use