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| Formula | C34H38O13 |
| Molar mass | 654.7 g·mol−1 |
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Silvestrol is a natural product from the flavagline family, with a cyclopenta[b] benzofuran core structure and an unusual dioxane ether side chain, which is found in the bark of trees from the genus Aglaia , especially Aglaia silvestris and Aglaia foveolata . [1]
It acts as a potent and selective inhibitor of the RNA helicase enzyme eIF4A, and has both broad-spectrum antiviral activity against diseases such as Ebola and coronaviruses, [2] [3] [4] [5] [6] and anti-cancer properties, [7] [8] which makes it of considerable interest in medical research. However, as it cannot be extracted from tree bark in commercial amounts and is prohibitively complex to produce synthetically, [9] practical applications have focused more on structurally simplified analogues such as CR-31-B. [10]
Antiviral drugs are a class of medication used for treating viral infections. Most antivirals target specific viruses, while a broad-spectrum antiviral is effective against a wide range of viruses. Antiviral drugs are one class of antimicrobials, a larger group which also includes antibiotic, antifungal and antiparasitic drugs, or antiviral drugs based on monoclonal antibodies. Most antivirals are considered relatively harmless to the host, and therefore can be used to treat infections. They should be distinguished from virucides, which are not medication but deactivate or destroy virus particles, either inside or outside the body. Natural virucides are produced by some plants such as eucalyptus and Australian tea trees.
Severe acute respiratory syndrome–related coronavirus is a species of virus consisting of many known strains phylogenetically related to severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) that have been shown to possess the capability to infect humans, bats, and certain other mammals. These enveloped, positive-sense single-stranded RNA viruses enter host cells by binding to the angiotensin-converting enzyme 2 (ACE2) receptor. The SARSr-CoV species is a member of the genus Betacoronavirus and of the subgenus Sarbecovirus.
Nucleoside analogues are structural analogues of a nucleoside, which normally contain a nucleobase and a sugar. Nucleotide analogues are analogues of a nucleotide, which normally has one to three phosphates linked to a nucleoside. Both types of compounds can deviate from what they mimick in a number of ways, as changes can be made to any of the constituent parts. They are related to nucleic acid analogues.
Aglaia foveolata is a species of tropical tree in the family Meliaceae. This plant occurs in Brunei, Indonesia, and Malaysia. It produces edible fruit. The bark contains silvestrol which is a potent inhibitor of ebola virus and Zika Virus replication.
Eukaryotic initiation factor 4A-I is a 46 kDa cytosolic protein that, in humans, is encoded by the EIF4A1 gene, which is located on chromosome 17. It is the most prevalent member of the eIF4A family of ATP-dependant RNA helicases, and plays a critical role in the initiation of cap-dependent eukaryotic protein translation as a component of the eIF4F translation initiation complex. eIF4A1 unwinds the secondary structure of RNA within the 5'-UTR of mRNA, a critical step necessary for the recruitment of the 43S preinitiation complex, and thus the translation of protein in eukaryotes. It was first characterized in 1982 by Grifo, et al., who purified it from rabbit reticulocyte lysate.
FGI-104 is the name of an experimental broad-spectrum antiviral drug, with activity against a range of viruses including hepatitis B, hepatitis C, HIV, Ebola virus, and Venezuelan equine encephalitis virus.
Antiviral proteins are proteins that are induced by human or animal cells to interfere with viral replication. These proteins are isolated to inhibit the virus from replicating in a host's cells and stop it from spreading to other cells. The Pokeweed antiviral protein and the Zinc-Finger antiviral protein are two major antiviral proteins that have undergone several tests for viruses, including HIV and influenza.
The 3C-like protease (3CLpro) or main protease (Mpro), formally known as C30 endopeptidase or 3-chymotrypsin-like protease, is the main protease found in coronaviruses. It cleaves the coronavirus polyprotein at eleven conserved sites. It is a cysteine protease and a member of the PA clan of proteases. It has a cysteine-histidine catalytic dyad at its active site and cleaves a Gln–(Ser/Ala/Gly) peptide bond.
3-Deazaneplanocin A is a drug which acts as both a S-adenosylhomocysteine synthesis inhibitor and also a histone methyltransferase EZH2 inhibitor. Studies have shown that it has effects in vitro against a variety of different tumor cell lines.
Favipiravir, sold under the brand name Avigan among others, is an antiviral medication used to treat influenza in Japan. It is also being studied to treat a number of other viral infections, including SARS-CoV-2. Like the experimental antiviral drugs T-1105 and T-1106, it is a pyrazinecarboxamide derivative.
Galidesivir is an antiviral drug, an adenosine analog. It was developed by BioCryst Pharmaceuticals with funding from NIAID, originally intended as a treatment for hepatitis C, but subsequently developed as a potential treatment for deadly filovirus infections such as Ebola virus disease and Marburg virus disease, as well as Zika virus. Currently, galidesivir is under phase 1 human trial in Brazil for coronavirus.
Scytovirin is a 95-amino acid antiviral protein isolated from the cyanobacteria Scytonema varium. It has been cultured in E. coli and its structure investigated in detail. Scytovirin is thought to be produced by the bacteria to protect itself from viruses that might otherwise attack it, but as it has broad-spectrum antiviral activity against a range of enveloped viruses, scytovirin has also been found to be useful against a range of major human pathogens, most notably HIV / AIDS but also including SARS coronavirus and filoviruses such as Ebola virus and Marburg virus. While some lectins such as cyanovirin and Urtica dioica agglutinin are thought likely to be too allergenic to be used internally in humans, studies so far on scytovirin and griffithsin have not shown a similar level of immunogenicity. Scytovirin and griffithsin are currently being investigated as potential microbicides for topical use.
FGI-106 is a broad-spectrum antiviral drug developed as a potential treatment for enveloped RNA viruses, in particular viral hemorrhagic fevers from the bunyavirus, flavivirus and filovirus families. It acts as an inhibitor which blocks viral entry into host cells. In animal tests FGI-106 shows both prophylactic and curative action against a range of deadly viruses for which few existing treatments are available, including the bunyaviruses hantavirus, Rift Valley fever virus and Crimean-Congo hemorrhagic fever virus, the flavivirus dengue virus, and the filoviruses Ebola virus and Marburg virus.
FGI-103 is an antiviral drug developed as a potential treatment for the filoviruses Ebola virus and Marburg virus. In tests on mice FGI-103 was effective against both Ebola and Marburg viruses when administered up to 48 hours after infection. The mechanism of action of FGI-103 has however not yet been established, as it was found not to be acting by any of the known mechanisms used by similar antiviral drugs.
NITD008 is an antiviral drug classified as an adenosine analog. It was developed as a potential treatment for flavivirus infections and shows broad spectrum antiviral activity against many related viruses such as dengue virus, West Nile virus, yellow fever virus, Powassan virus, hepatitis C virus, Kyasanur Forest disease virus, Omsk hemorrhagic fever virus, and Zika virus. However, NITD008 proved too toxic in pre-clinical animal testing to be suitable for human trials, but it continues to be used in research to find improved treatments for emerging viral diseases.
Brequinar (DuP-785) is a drug that acts as a potent and selective inhibitor of the enzyme dihydroorotate dehydrogenase. It blocks synthesis of pyrimidine based nucleotides in the body and so inhibits cell growth. Brequinar was invented by DuPont Pharmaceuticals in the 1980s. In 2001, Bristol-Myers Squibb acquired DuPont, and in 2017, Clear Creek Bio acquired the rights to brequinar from BMS.
GC376 is a broad-spectrum antiviral medication under development by the biopharmaceutical company Anivive Lifesciences for therapeutic uses in humans and animals. Anivive licensed the exclusive worldwide patent rights to GC376 from Kansas State University. As of 2020, GC376 is being investigated as treatment for COVID-19. GC376 shows activity against many human and animal viruses including coronavirus and norovirus; the most extensive research has been multiple in vivo studies in cats treating a coronavirus which causes deadly feline infectious peritonitis. Other research supports use in porcine epidemic diarrhea virus.
Broad-spectrum antivirals (BSAs) are a class of molecules or compounds, which inhibit the infection of multiple viruses from the same or different virus families. BSAs could be divided into experimental and investigational agents, and approved drugs. BSAs work by inhibiting viral proteins or by targeting host cell factors and processes exploited by different viruses during infection. As of 2021, there are 150 known BSAs in varying stages of development, effective against 78 human viruses. BSAs are potential candidates for treatment of emerging and re-emerging viruses, such as ebola, marburg, and SARS-CoV-2. Many BSAs show antiviral activity against other viruses than originally investigated. Efforts in drug repurposing for SARS-CoV-2 is currently underway. A database of BSAs and viruses they inhibit could be found here.
Sangivamycin is a natural product originally isolated from Streptomyces rimosus, which is a nucleoside analogue. It acts as an inhibitor of protein kinase C. It has antibiotic, antiviral and anti-cancer properties and has been investigated for various medical applications, though never approved for clinical use itself. However, a number of related derivatives continue to be researched.
S416 (GTPL-11164) is a drug which acts as a selective inhibitor of the enzyme dihydroorotate dehydrogenase (DHODH). This enzyme is involved in the synthesis of pyrimidine nucleosides in the body, which are required for the synthesis of DNA and RNA. This is an important rate-limiting step in the replication of viruses, and so DHODH inhibitors may have applications as broad-spectrum antiviral drugs. In tests in vitro, S416 was found to have antiviral activity against a range of pathogenic RNA viruses including influenza, Zika virus, Ebola virus and SARS-CoV-2.
