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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 -
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 -
Archives of Disease in Childhood Aug 1970The therapeutic effect of methisazone was studied in a group of 50 children who were suffering from infective complications of smallpox vaccination, such as ectopic...
The therapeutic effect of methisazone was studied in a group of 50 children who were suffering from infective complications of smallpox vaccination, such as ectopic primary lesions of the orbit, face, or mouth, eczema vaccinatum, and vaccinia. In 16 children with ectopic lesions who were treated with methisazone by mouth in total doses of 3·2-14·0 g., the mean healing time was 13·3 days, compared with 17·8 days in a control group of 23 similarly infected children who were not treated with methisazone. The difference did not attain significance, but there was a highly significant difference (p<0·01) in the number of cases in which healing occurred within 6 days (13 in the methisazone group and 6 in the control group). In 5 children accidental infection with vaccinia occurred, though antivaccinial γ-globulin had been given 5-10 days previously. Methisazone was also given to 4 children with eczema vaccinatum and 2 with localized vaccinia gangrenosa. The treatment appeared to be beneficial in comparison with control groups of 3 and 2 children, respectively, but the groups were too small for precise assessment. Methisazone appeared to accelerate the healing of the lesions in 3 children when applied locally.
Topics: Antiviral Agents; Child; Child, Preschool; Eczema; Facial Dermatoses; Female; Humans; Infant; Male; Orbit; Smallpox Vaccine; Thiosemicarbazones; Vaccinia
PubMed: 5506947
DOI: 10.1136/adc.45.242.573 -
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 -
British Medical Journal Sep 1964
Topics: Methisazone; Toxicology
PubMed: 14171075
DOI: No ID Found -
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 -
Antimicrobial Agents and Chemotherapy Jan 1972The antiviral drug methisazone (N-methylisatin beta-thiosemicarbazone) was tested for its effect on immune responses to sheep erythrocytes and on hemopoietic...
The antiviral drug methisazone (N-methylisatin beta-thiosemicarbazone) was tested for its effect on immune responses to sheep erythrocytes and on hemopoietic colony-forming cell (granulocyte-macrophage progenitor cell) responses to complete Freund's adjuvant in mice. Suppressive activity was demonstrated in both systems, the immune system being more readily and more consistently susceptible. Evidence is presented which suggests that the insoluble particulate form of the drug has both stimulatory and suppressive effects on the colony-forming cell system, whereas the soluble form is only suppressive. Methisazone increased the mortality from ectromelia in adjuvant-treated animals.
Topics: Animals; Antiviral Agents; Bone Marrow Cells; Cells, Cultured; Erythrocytes; Female; Hematopoiesis; Immunosuppression Therapy; Indoles; Mice; Mice, Inbred C57BL; Sheep; Spleen; Thiosemicarbazones
PubMed: 4670426
DOI: 10.1128/AAC.1.1.1 -
Antimicrobial Agents and Chemotherapy Jan 1972Methisazone (N-methylisatin beta-thiosemicarbazone) was shown to inhibit the development of hemopoietic colonies in vitro when incorporated in the culture medium. The...
Methisazone (N-methylisatin beta-thiosemicarbazone) was shown to inhibit the development of hemopoietic colonies in vitro when incorporated in the culture medium. The activity of methisazone was compared with that of several antimetabolic and antibiotic drugs. Although methisazone reduced the number of colonies, it did not affect the size of those colonies which did develop, and evidence is presented which shows that it acted only at the early stages of colony development. Some implications of these findings are briefly discussed.
Topics: Animals; Antiviral Agents; Bone Marrow; Bone Marrow Cells; Cells, Cultured; Endotoxins; Mice; Mice, Inbred C57BL; Rifampin; Thiosemicarbazones; Time Factors
PubMed: 4670431
DOI: 10.1128/AAC.1.1.6 -
Canadian Medical Association Journal Jul 1967
Topics: Antiviral Agents; Female; Gangrene; Herpes Simplex; Humans; Immunotherapy; Middle Aged; Smallpox Vaccine; Thiosemicarbazones; Vaccinia
PubMed: 6028473
DOI: No ID Found