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International Journal of Molecular... Mar 2021SARS-CoV-2 currently lacks effective first-line drug treatment. We present promising data from in silico docking studies of new Methisazone compounds (modified with...
SARS-CoV-2 currently lacks effective first-line drug treatment. We present promising data from in silico docking studies of new Methisazone compounds (modified with calcium, Ca; iron, Fe; magnesium, Mg; manganese, Mn; or zinc, Zn) designed to bind more strongly to key proteins involved in replication of SARS-CoV-2. In this in silico molecular docking study, we investigated the inhibiting role of Methisazone and the modified drugs against SARS-CoV-2 proteins: ribonucleic acid (RNA)-dependent RNA polymerase (RdRp), spike protein, papain-like protease (PlPr), and main protease (MPro). We found that the highest binding interactions were found with the spike protein (6VYB), with the highest overall binding being observed with Mn-bound Methisazone at -8.3 kcal/mol, followed by Zn and Ca at -8.0 kcal/mol, and Fe and Mg at -7.9 kcal/mol. We also found that the metal-modified Methisazone had higher affinity for PlPr and MPro. In addition, we identified multiple binding pockets that could be singly or multiply occupied on all proteins tested. The best binding energy was with Mn-Methisazone versus spike protein, and the largest cumulative increases in binding energies were found with PlPr. We suggest that further studies are warranted to identify whether these compounds may be effective for treatment and/or prophylaxis.
Topics: Antiviral Agents; Calcium; Coronavirus 3C Proteases; Coronavirus Papain-Like Proteases; Coronavirus RNA-Dependent RNA Polymerase; Drug Design; Humans; Iron; Magnesium; Manganese; Metals; Methisazone; Models, Molecular; Molecular Docking Simulation; Molecular Dynamics Simulation; Protein Binding; SARS-CoV-2; Spike Glycoprotein, Coronavirus; Zinc; COVID-19 Drug Treatment
PubMed: 33804129
DOI: 10.3390/ijms22062977 -
Life Sciences Jul 2020The severe acute respiratory syndrome coronavirus 2, better known as COVID-19 has become the current health concern to the entire world. Initially appeared in Wuhan,...
AIMS
The severe acute respiratory syndrome coronavirus 2, better known as COVID-19 has become the current health concern to the entire world. Initially appeared in Wuhan, China around December 2019, it had spread to almost 187 countries due to its high contagious nature. Precautionary measures remain the sole obliging tactic to cease the person to person transmissions till any effective method of treatment or vaccine is developed. Amidst the pandemic, research and development of new molecule is labour-intensive and tedious process. Drug repurposing is the concept of identifying therapeutically potent molecule from the library of pre-existing molecules.
MATERIALS AND METHODS
In the present study, 61 molecules that are already being used in clinics or under clinical scrutiny as antiviral agents are surveyed via docking study. Docking study was performed using Maestro interface (Schrödinger Suite, LLC, NY).
KEY FINDINGS
Out of these 61 molecules, 37 molecules were found to interact with >2 protein structures of COVID-19. The docking results indicate that amongst the reported molecules, HIV protease inhibitors and RNA-dependent RNA polymerase inhibitors showed promising features of binding to COVID-19 enzyme. Along with these, Methisazone an inhibitor of protein synthesis, CGP42112A an angiotensin AT2 receptor agonist and ABT450 an inhibitor of the non-structural protein 3-4A might become convenient treatment option as well against COVID-19.
SIGNIFICANCE
The drug repurposing approach provide an insight about the therapeutics that might be helpful in treating corona virus disease.
Topics: Antiviral Agents; Betacoronavirus; COVID-19; Computer Simulation; Coronavirus 3C Proteases; Coronavirus Infections; Cysteine Endopeptidases; Drug Repositioning; Molecular Docking Simulation; Pandemics; Pneumonia, Viral; SARS-CoV-2; Viral Nonstructural Proteins
PubMed: 32278693
DOI: 10.1016/j.lfs.2020.117652 -
Vaccine Jul 2019West Nile virus (WNV) is the most frequent mosquito-borne disease reported in the continental United States and although an effective veterinary vaccine exists for...
West Nile virus (WNV) is the most frequent mosquito-borne disease reported in the continental United States and although an effective veterinary vaccine exists for horses, there is still no commercial vaccine approved for human use. We have previously tested a 3% hydrogen peroxide (HO)-based WNV inactivation approach termed, HydroVax, in Phase I clinical trials and the vaccine was found to be safe and modestly immunogenic. Here, we describe an advanced, next-generation oxidation approach (HydroVax-II) for the development of inactivated vaccines that utilizes reduced concentrations of HO in combination with copper (cupric ions, Cu) complexed with the antiviral compound, methisazone (MZ). Further enhancement of this oxidative approach included the addition of a low percentage of formaldehyde, a cross-linking reagent with a different mechanism of action that, together with HO/Cu/MZ, provides a robust two-pronged approach to virus inactivation. Together, this new approach results in rapid virus inactivation while greatly improving the maintenance of WNV-specific neutralizing epitopes mapped across the three structural domains of the WNV envelope protein. In combination with more refined manufacturing techniques, this inactivation technology resulted in vaccine-mediated WNV-specific neutralizing antibody responses that were 130-fold higher than that observed using the first generation, HO-only vaccine approach and provided 100% protection against lethal WNV infection. This new approach to vaccine development represents an important area for future investigation with the potential not only for improving vaccines against WNV, but other clinically relevant viruses as well.
Topics: Animals; Cell Line; Chlorocebus aethiops; Female; Horse Diseases; Horses; Humans; Mice; Mice, Inbred BALB C; Vaccines, Inactivated; Vaccinology; Vero Cells; Virus Inactivation; West Nile Fever; West Nile Virus Vaccines; West Nile virus
PubMed: 30606462
DOI: 10.1016/j.vaccine.2018.12.020 -
Clinical Infectious Diseases : An... Dec 2004The potential consequences of a competently executed smallpox attack have not been adequately considered by policy makers. The possibility of release of an aerosolized... (Review)
Review
The potential consequences of a competently executed smallpox attack have not been adequately considered by policy makers. The possibility of release of an aerosolized and/or bioengineered virus must be anticipated and planned for. The transmission and infectivity of variola virus are examined. Arguments for and against pre-event vaccination are offered. The likely morbidity and mortality that would ensue from implementation of a mass pre-event vaccination program, within reasonable boundaries, are known. The extent of contagion that could result from an aerosolized release of virus is unknown and may have been underestimated. Pre-event vaccination of first responders is urged, and voluntary vaccination programs should be offered to the public. Two defenses against a vaccine-resistant, engineered variola virus are proposed for consideration. Methisazone, an overlooked drug, is reported to be effective for prophylaxis only. The extent of reduction in the incidence of smallpox with use of this agent is uncertain. It is useless for treatment of clinical smallpox. N-100 respirators (face masks) worn by uninfected members of the public may prevent transmission of the virus.
Topics: Biological Warfare; Humans; Smallpox; Smallpox Vaccine
PubMed: 15578369
DOI: 10.1086/425745 -
Antiviral Research Jan 2003Several animal models using mice (most frequently), rabbits, or monkeys have been used to identify compounds active against orthopoxvirus infections. The treatment of... (Review)
Review
Several animal models using mice (most frequently), rabbits, or monkeys have been used to identify compounds active against orthopoxvirus infections. The treatment of vaccinia virus infections has been well studied in models involving infection of scarified skin or eyes, or resulting from intravenous, intraperitoneal, intracerebral, or intranasal virus inoculation. Cowpox virus has been used in intranasal or aerosol infection studies to evaluate the treatment of lethal respiratory infections. Rabbitpox, monkeypox, and variola viruses have been employed to a lesser extent than the other viruses in chemotherapy experiments. A review of the literature over the past 50 years has identified a number of compounds effective in treating one or more of these infections, which include thiosemicarbazones, nucleoside and nucleotide analogs, interferon, interferon inducers, and other unrelated compounds. Substances that appear to have the greatest potential as anti-orthopoxvirus agents are the acyclic nucleotides, (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (cidofovir, HPMPC) and 1-[((S)-2-hydroxy-2-oxo-1,4,2-dioxaphosphorinan-5-yl)methyl]cytosine (cyclic HPMPC), and the acyclic nucleoside analog, 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine (S2242). Other classes of compounds that have not been sufficiently studied in lethal infection models and deserve further consideration are thiosemicarbazones related to methisazone, and analogs of adenosine-N(1)-oxide and 1-(benzyloxy)adenosine.
Topics: Animals; Antiviral Agents; Bioterrorism; Cidofovir; Cytosine; Disease Models, Animal; Humans; Mice; Mice, SCID; Nucleosides; Organophosphonates; Organophosphorus Compounds; Orthopoxvirus; Poxviridae Infections; Rabbits; Smallpox; Thiosemicarbazones
PubMed: 12615302
DOI: 10.1016/s0166-3542(02)00199-7 -
Antiviral Research Jan 2003We assessed the activities of 24 different antiviral compounds against smallpox (two strains of variola major and one of variola minor), monkeypox, vaccinia and cowpox...
We assessed the activities of 24 different antiviral compounds against smallpox (two strains of variola major and one of variola minor), monkeypox, vaccinia and cowpox viruses by a neutral red uptake assay. To establish assay parameters, we examined viral replication and its inhibition at various times postinfection and at several multiplicities of infection. Drugs were selected to target a range of functions involved in viral replication. Eight compounds (cidofovir, cyclic HPMPC (cHPMPC), HPMPA, ribavirin, tiazofurin, carbocyclic 3-deazaadenosine, 3-deazaneplanocin A and DFBA (1-(2,4-difluorobenzyloxy)adenosine perchlorate)-a derivative of adenosine N1-oxide) inhibited the replication of all three variola strains and the other orthopoxviruses at drug concentrations within a pharmacologically achievable range. Two others (methisazone and bis-POM-PMEA) showed a lesser degree of antiviral effect, while the remainder were inactive. To examine possible naturally occurring drug resistance among a large number of variola isolates obtained from different geographical regions and at different times, we examined the sensitivity of 35 different strains of variola as well as other orthopoxviruses to a subset of three of the most active compounds: cidofovir, cHPMPC, and ribavirin. Preliminary data indicate that nearly all isolates appear to have similar drug sensitivities. These findings are currently being verified and expanded.
Topics: Animals; Antiviral Agents; Cell Line; Chlorocebus aethiops; Humans; Microbial Sensitivity Tests; Monkeypox virus; Neutral Red; Orthopoxvirus; Poxviridae Infections; Variola virus; Vero Cells; Viral Plaque Assay; Virus Replication
PubMed: 12615299
DOI: 10.1016/s0166-3542(02)00196-1 -
Antimicrobial Agents and Chemotherapy Nov 1993N-Methylisatin-beta-4',4'-diethylthiosemicarbazone (M-IBDET) and N-allylisatin-beta-4',4'-diallylthiosemicarbazone (A-IBDAT) selectively inhibited v-abl protein (P120),...
N-Methylisatin-beta-4',4'-diethylthiosemicarbazone (M-IBDET) and N-allylisatin-beta-4',4'-diallylthiosemicarbazone (A-IBDAT) selectively inhibited v-abl protein (P120), an oncogene product associated with tyrosine kinase activity. Concentrations of M-IBDET ranging between 0.17 and 0.64 microM and concentrations of A-IBDAT from 1.45 to 2.9 microM reduced tyrosine kinase activity significantly, whereas 0.64 microM M-IBDET and 2.9 microM A-IBDAT blocked P120 production. Cellular growth rate, protein production, and synthesis of p45 actin and p53 nuclear oncogene were not affected at these conditions. M-IBDET and A-IBDAT selectively suppress the v-abl oncogene as well as Moloney murine leukemia virus production.
Topics: Abelson murine leukemia virus; Animals; Cell Line; Electrophoresis, Polyacrylamide Gel; Isatin; Methisazone; Mice; Moloney murine leukemia virus; Oncogene Proteins v-abl; Protein-Tyrosine Kinases; Thiosemicarbazones; Virus Replication
PubMed: 8285639
DOI: 10.1128/AAC.37.11.2483 -
Antimicrobial Agents and Chemotherapy Nov 1987The mode of inhibition of N-methylisatin-beta-4',4'-diethylthiosemicarbazone (M-IBDET) on Moloney leukemia virus production was studied. Drug treatment of infected cells...
The mode of inhibition of N-methylisatin-beta-4',4'-diethylthiosemicarbazone (M-IBDET) on Moloney leukemia virus production was studied. Drug treatment of infected cells did not alter the amounts or sizes of the 35S and 22S subgenomic viral RNAs. The translation abilities of poly(A)+ RNA derived from M-IBDET-treated cells was also unaffected, as judged by cell-free translation analysis. Poly(A)+ RNA derived from M-IBDET-treated cells directed translation of equal amounts of viral gag precursors, gPr-80gag and Pr-65gag, as did poly(A)+ RNA prepared from untreated cells. The addition of M-IBDET to a cell-free translation system programmed with either total poly(A)+ RNA extracted from infected cells or hybrid-selected viral RNA inhibited the synthesis of viral protein precursors. An examination of the effect of M-IBDET on polysomes engaged in the translation of viral proteins revealed a fourfold accumulation of polysomal virus-specific RNA in drug-treated cells. These results suggest that the inhibition of Moloney leukemia virus by M-IBDET involves a block in the translation of viral RNA rather than interference with viral RNA transcription.
Topics: Gene Products, gag; Methisazone; Moloney murine leukemia virus; Polyribosomes; Protein Biosynthesis; RNA, Messenger; RNA, Viral; Retroviridae Proteins; Thiosemicarbazones; Transcription, Genetic; Viral Proteins
PubMed: 3501701
DOI: 10.1128/AAC.31.11.1798 -
Antimicrobial Agents and Chemotherapy Dec 1984The mechanism of inhibition of Moloney leukemia virus by N-methylisatin-beta-4',4'-diethylthiosemicarbazone was studied. Experiments that used [3H]leucine for...
The mechanism of inhibition of Moloney leukemia virus by N-methylisatin-beta-4',4'-diethylthiosemicarbazone was studied. Experiments that used [3H]leucine for short-pulse labeling in the presence of the drug resulted in a 71% inhibition in the synthesis of Pr-80, the polypeptide precursor of the gag viral proteins. The radioactive pulse products of the polypeptide precursors after a further 2-h chase period showed a normal cleavage of the precursors, with the formation of a reduced amount of final mature viral structural proteins. The experimental evidence indicated that at the inhibitory concentration of 17 microM N-methylisatin-beta-4',4'-diethylthiosemicarbazone, the amount of intracellular viral RNA was not affected, whereas the activities of reverse transcriptase and the other viral protein syntheses were suppressed.
Topics: Animals; Antiviral Agents; Cell Line; Centrifugation, Density Gradient; Methisazone; Mice; Moloney murine leukemia virus; Precipitin Tests; RNA, Viral; RNA-Directed DNA Polymerase; Thiosemicarbazones; Viral Proteins; Virus Replication
PubMed: 6084472
DOI: 10.1128/AAC.26.6.913 -
Antimicrobial Agents and Chemotherapy Aug 1973The 1-methylisatin derivative of isatin thiosemicarbazone was previously shown to inhibit granulocyte-macrophage colony growth in vitro by an action at the early stages...
The 1-methylisatin derivative of isatin thiosemicarbazone was previously shown to inhibit granulocyte-macrophage colony growth in vitro by an action at the early stages of colony development. The parent compound isatin thiosemicarbazone and 25 other derivatives were tested, and a wide range of activity was found (50% colony inhibition from 0.07 to > 100 mug per ml of culture). High activity was not associated with any specific substituent although 1-methyl or 1-ethyl isatin groups in association with 4'4' morpholino or 4'4' tetramethylene thiosemicarbazone substitutions were within the most active group. No correlation between the antimarrow and known antiviral activities of these compounds was apparent. Two of the more active compounds were compared with methisazone and were shown to have the same property of selective action on the early stages of granulocyte-macrophage differentiation in culture. It is suggested that this group of compounds might possibly provide some useful antileukemia agents.
Topics: Bone Marrow; Bone Marrow Cells; Cells, Cultured; Humans; Indoles; Leukocytes; Macrophages; Thiosemicarbazones
PubMed: 4790931
DOI: 10.1128/AAC.4.2.105