The part of the influenza polymerase PA subunit featuring endonuclease activity is a target for anti-influenza therapies, including the FDA-approved drug Xofluza. A general feature of endonuclease inhibitors is their ability to chelate Mg2+ or Mn2+ ions located in the enzyme's catalytic site. Previously, we screened a panel of flavonoids for PA inhibition and found luteolin and its C-glucoside orientin to be potent inhibitors. Through structural analysis, we identified the presence of a 3',4'-dihydroxyphenyl moiety as a crucial feature for sub-micromolar inhibitory activity. Here, we report results from a subsequent investigation exploring structural changes at the C-7 and C-8 positions of luteolin. Experimental IC50 values were determined by AlphaScreen technology. The most potent inhibitors were C-8 derivatives with inhibitory potencies comparable to that of luteolin. Bio-isosteric replacement of the C-7 hydroxyl moiety of luteolin led to a series of compounds with one-order-of-magnitude-lower inhibitory potencies. Using X-ray crystallography, we solved structures of the wild-type PA-N-terminal domain and its I38T mutant in complex with orientin at 1.9 Å and 2.2 Å resolution, respectively.
Drug compounds including memantine moieties are an important group of biologically active agents for different pathologies, including the Alzheimer's disease. In the present study, a series of memantine derivatives incorporating amino acid residues have been synthesized and their neuroprotective in vitro evaluation in respect of the Alzheimer's disease, involving the effects on the resistance to Aβ toxicity, excitotoxicity, oxidative stress, hypoxia, and neuroinflammation has been studied. The cytotoxicities of the compounds were detected by CPE assay. TC50 and IC50 were determined using Reed and Muench method. Solubility and distribution were measured using a shake-flask method. Permeability of the compounds was studied using Franz diffusion cell and Permeapad™ barrier. These compounds displayed apparent multi-neuroprotective effects against copper-triggered Aβ toxicity, glutamate-induced excitotoxicity, and oxidative and hypoxic injuries. They also showed the ability to inhibit the inflammatory cytokine release from the activated microglia and potential anti-neuroinflammatory effects. Especially, two most promising compounds H-4-F-Phe-memantine and H-Tyr-memantine demonstrated the equivalent functional bioactivities in comparison with the positive control memantine hydrochloride. Higher solubility in muriatic buffer than in phosphate buffer was detected. The distribution coefficients showed the optimal lipophilicity for compounds. The presented results propose new class of memantine derivatives as potential drug compounds. Based on the experimental results, the correlations have been obtained between the biological, physicochemical parameters and structural descriptors. The correlation equations have been proposed to predict the properties of new memantine derivatives knowing only the structural formula.
- MeSH
- Alzheimerova nemoc farmakoterapie genetika patologie MeSH
- amyloidní beta-protein účinky léků toxicita MeSH
- buňky MDCK MeSH
- chřipka lidská farmakoterapie virologie MeSH
- kyselina glutamová metabolismus MeSH
- lidé MeSH
- memantin analogy a deriváty chemie farmakologie MeSH
- neuroprotektivní látky chemie farmakologie MeSH
- Orthomyxoviridae účinky léků patogenita MeSH
- oxidační stres účinky léků MeSH
- psi MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- psi MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
A series of nineteen amino acid analogues of amantadine (Amt) and rimantadine (Rim) were synthesized and their antiviral activity was evaluated against influenza virus A (H3N2). Among these analogues, the conjugation of rimantadine with glycine illustrated high antiviral activity combined with low cytotoxicity. Moreover, this compound presented a profoundly high stability after in vitro incubation in human plasma for 24 h. Its thermal stability was established using differential and gravimetric thermal analysis. The crystal structure of glycyl-rimantadine revealed that it crystallizes in the orthorhombic Pbca space group. The structure-activity relationship for this class of compounds was established, with CoMFA (Comparative Molecular Field Analysis) 3D-Quantitative Structure Activity Relationships (3D-QSAR) studies predicting the activities of synthetic molecules. In addition, molecular docking studies were conducted, revealing the structural requirements for the activity of the synthetic molecules.
- MeSH
- adamantan analogy a deriváty chemická syntéza chemie farmakologie MeSH
- antivirové látky chemická syntéza chemie farmakologie MeSH
- buněčná smrt účinky léků MeSH
- buňky MDCK MeSH
- diferenční termická analýza MeSH
- krystalografie rentgenová MeSH
- kvantitativní vztahy mezi strukturou a aktivitou * MeSH
- lidé MeSH
- metoda nejmenších čtverců MeSH
- molekulární konformace MeSH
- Orthomyxoviridae účinky léků MeSH
- počítačová simulace * MeSH
- proteinové domény MeSH
- proteiny virové matrix chemie MeSH
- psi MeSH
- rimantadin krev chemie MeSH
- simulace molekulového dockingu MeSH
- stabilita léku MeSH
- teplota MeSH
- vazebná místa MeSH
- vodíková vazba MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- psi MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- adamantan farmakokinetika farmakologie terapeutické užití MeSH
- antimetabolity farmakokinetika farmakologie terapeutické užití MeSH
- antivirové látky * farmakokinetika farmakologie terapeutické užití MeSH
- chřipka lidská farmakoterapie klasifikace MeSH
- herpetické infekce farmakoterapie klasifikace MeSH
- humanizované monoklonální protilátky terapeutické užití MeSH
- inhibitory enzymů terapeutické užití MeSH
- koronavirové infekce MeSH
- lidé MeSH
- lidský respirační syncytiální virus účinky léků MeSH
- nemoci dýchací soustavy * etiologie farmakoterapie MeSH
- neuraminidasa aplikace a dávkování MeSH
- nukleosidy farmakokinetika farmakologie terapeutické užití MeSH
- Orthomyxoviridae účinky léků MeSH
- virus SARS účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
The threat of a worldwide influenza pandemic has greatly increased over the past decade with the emergence of highly virulent avian influenza strains. The increased frequency of drug-resistant influenza strains against currently available antiviral drugs requires urgent development of new strategies for antiviral therapy, too. The research in the field of therapeutic peptides began to develop extensively in the second half of the 20(th) century. Since then, the mechanisms of action for several peptides and their antiviral prospect received large attention due to the global threat posed by viruses. Here, we discussed the therapeutic properties of peptides used in influenza treatment. Peptides with antiviral activity against influenza can be divided into three main groups. First, entry blocker peptides such as a Flupep that interact with influenza hemagglutinin, block its binding to host cells and prevent viral fusion. Second, several peptides display virucidal activity, disrupting viral envelopes, e.g., Melittin. Finally, a third set of peptides interacts with the viral polymerase complex and act as viral replication inhibitors such as PB1 derived peptides. Here, we present a review of the current literature describing the antiviral activity, mechanism and future therapeutic potential of these influenza antiviral peptides.
- MeSH
- antivirové látky farmakologie terapeutické užití MeSH
- chřipka lidská farmakoterapie MeSH
- infekce viry z čeledi Orthomyxoviridae farmakoterapie MeSH
- internalizace viru účinky léků MeSH
- klinické zkoušky jako téma MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- objevování léků trendy MeSH
- Orthomyxoviridae účinky léků fyziologie MeSH
- peptidy farmakologie terapeutické užití MeSH
- replikace viru účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Chemotherapy of viral infections is still challenging. Salicylanilides demonstrated a wide range of biological activities including antiviral potency and the review summarizes this field. Niclosamide was described to be able to affect coronaviruses. Some salicylanilides and salicylamides could inhibit HIV virus by targeting of HIV-1 integrase or reverse transcriptase. Hepatitis C virus is another virus, which could be potentially afflicted by salicylanilides on the level of two enzymes--NS3 protease and NS5B RNA polymerase. Nitazoxanide is a nitrothiazole derivative of salicylamide useful for the treatment of protozoal and bacterial infections with an extended range of antiviral activity and innovative mechanism of action, especially against hepatitis and influenza viruses or rotaviruses. Nitazoxanide, its metabolite tizoxanide and their derivatives are a very promising stream in the development of new antiviral compounds. In this review, we summarize the antiviral activity of structures containing salicylanilide and partly salicylamide moiety.
- MeSH
- antivirové látky chemická syntéza chemie farmakologie MeSH
- Hepacivirus účinky léků MeSH
- HIV-1 účinky léků MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- Orthomyxoviridae účinky léků MeSH
- Rotavirus účinky léků MeSH
- salicylanilidy chemická syntéza chemie farmakologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Two selective acylation methods for silybin esterification with long-chain fatty acids were developed, yielding a series of silybin 7-O- and 23-O-acyl-derivatives of varying acyl chain lengths. These compounds were tested for their antioxidant (inhibition of lipid peroxidation and DPPH-scavenging) and anti-influenza virus activities. The acyl chain length is an important prerequisite for both biological activities, as they improved with increasing length of the acyl moiety.
- MeSH
- acylace MeSH
- antioxidancia farmakologie MeSH
- antivirové látky farmakologie MeSH
- buněčné linie MeSH
- esterifikace MeSH
- magnetická rezonanční spektroskopie MeSH
- mastné kyseliny farmakologie MeSH
- molekulární struktura MeSH
- Orthomyxoviridae účinky léků MeSH
- psi MeSH
- silymarin farmakologie MeSH
- viabilita buněk účinky léků MeSH
- zvířata MeSH
- Check Tag
- psi MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- antivirové látky chemie toxicita MeSH
- cinnamáty MeSH
- estery cholesterolu MeSH
- Orthomyxoviridae účinky léků MeSH
- Publikační typ
- srovnávací studie MeSH
Journal of infectious diseases, ISSN 0022-1899 Supplement Vol.176. 1
90 s. : il. ; 30 cm
