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1.
Biomolecules ; 11(12)2021 12 10.
Article in English | MEDLINE | ID: covidwho-1572360

ABSTRACT

Metal-based drugs represent a rich source of chemical substances of potential interest for the treatment of COVID-19. To this end, we have developed a small but representative panel of nine metal compounds, including both synthesized and commercially available complexes, suitable for medical application and tested them in vitro against the SARS-CoV-2 virus. The screening revealed that three compounds from the panel, i.e., the organogold(III) compound Aubipyc, the ruthenium(III) complex KP1019, and antimony trichloride (SbCl3), are endowed with notable antiviral properties and an acceptable cytotoxicity profile. These initial findings prompted us to perform a computational study to unveil the likely molecular basis of their antiviral actions. Calculations evidenced that the metalation of nucleophile sites in SARS-CoV-2 proteins or nucleobase strands, induced by Aubipyc, SbCl3, and KP1019, is likely to occur. Remarkably, we found that only the deprotonated forms of Cys and Sec residues can react favorably with these metallodrugs. The mechanistic implications of these findings are discussed.


Subject(s)
2,2'-Dipyridyl/analogs & derivatives , Antimony/pharmacology , Antiviral Agents/pharmacology , COVID-19/drug therapy , Chlorides/pharmacology , Indazoles/pharmacology , Organogold Compounds/pharmacology , Organometallic Compounds/pharmacology , Ruthenium Compounds/pharmacology , SARS-CoV-2/drug effects , 2,2'-Dipyridyl/chemistry , 2,2'-Dipyridyl/pharmacology , Animals , Antimony/chemistry , Antiviral Agents/chemistry , Cell Line , Chlorides/chemistry , Chlorocebus aethiops , Drug Discovery , Humans , Indazoles/chemistry , Organogold Compounds/chemistry , Organometallic Compounds/chemistry , Ruthenium Compounds/chemistry , Vero Cells
2.
Viruses ; 13(8)2021 08 15.
Article in English | MEDLINE | ID: covidwho-1355053

ABSTRACT

We compared the electrostatic properties of the spike proteins (S-proteins) of three coronaviruses, SARS-CoV, MERS-CoV, and SARS-CoV-2, and their interactions with photosensitizers (PSs), octacationic octakis(cholinyl)zinc phthalocyanine (Zn-PcChol8+) and monocationic methylene blue (MB). We found a major common PS binding site at the connection of the S-protein stalk and head. The molecules of Zn-PcChol8+ and MB also form electrostatic encounter complexes with large area of negative electrostatic potential at the head of the S-protein of SARS-CoV-2, between fusion protein and heptad repeat 1 domain. The top of the SARS-CoV spike head demonstrates a notable area of electrostatic contacts with Zn-PcChol8+ and MB that corresponds to the N-terminal domain. The S-protein protomers of SARS-CoV-2 in "open" and "closed" conformations demonstrate different ability to attract PS molecules. In contrast with Zn-PcChol8+, MB possesses the ability to penetrate inside the pocket formed as a result of SARS-CoV-2 receptor binding domain transition into the "open" state. The existence of binding site for cationic PSs common to the S-proteins of SARS-CoV, SARS-CoV-2, and MERS-CoV creates prospects for the wide use of this type of PSs to combat the spread of coronaviruses.


Subject(s)
Choline/metabolism , Indoles/metabolism , Isoindoles/metabolism , Middle East Respiratory Syndrome Coronavirus/chemistry , Organometallic Compounds/metabolism , Photosensitizing Agents/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Zinc Compounds/metabolism , Binding Sites , Indoles/chemistry , Methylene Blue/metabolism , Models, Molecular , Molecular Dynamics Simulation , Organometallic Compounds/chemistry , Protein Conformation , Protein Domains , Protein Subunits/chemistry , SARS Virus/chemistry , SARS-CoV-2/chemistry , Spike Glycoprotein, Coronavirus/chemistry , Static Electricity
3.
Eur J Med Chem ; 224: 113696, 2021 Nov 15.
Article in English | MEDLINE | ID: covidwho-1300086

ABSTRACT

The antimicrobial resistance (AMR) is an intractable problem for the world. Metal ions are essential for the cell process and biological function in microorganisms. Many metal-based complexes with the potential for releasing ions are more likely to be absorbed for their higher lipid solubility. Hence, this review highlights the clinical potential of organometallic compounds for the treatment of infections caused by bacteria or fungi in recent five years. The common scaffolds, including antimicrobial peptides, N-heterocyclic carbenes, Schiff bases, photosensitive-grand-cycle skeleton structures, aliphatic amines-based ligands, and special metal-based complexes are summarized here. We also discuss their therapeutic targets and the risks that should be paid attention to in the future studies, aiming to provide information for researchers on metal-based complexes as antimicrobial agents and inspire the design and synthesis of new antimicrobial drugs.


Subject(s)
Anti-Bacterial Agents/pharmacology , Antifungal Agents/pharmacology , Bacteria/drug effects , Drug Discovery , Fungi/drug effects , Organometallic Compounds/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Antifungal Agents/chemical synthesis , Antifungal Agents/chemistry , Microbial Sensitivity Tests , Molecular Structure , Organometallic Compounds/chemical synthesis , Organometallic Compounds/chemistry
4.
Viruses ; 13(6)2021 05 25.
Article in English | MEDLINE | ID: covidwho-1244147

ABSTRACT

SARS-CoV-2 emerged in 2019 as a devastating viral pathogen with no available preventative or treatment to control what led to the current global pandemic. The continued spread of the virus and increasing death toll necessitate the development of effective antiviral treatments to combat this virus. To this end, we evaluated a new class of organometallic complexes as potential antivirals. Our findings demonstrate that two pentamethylcyclopentadienyl (Cp*) rhodium piano stool complexes, Cp*Rh(1,3-dicyclohexylimidazol-2-ylidene)Cl2 (complex 2) and Cp*Rh(dipivaloylmethanato)Cl (complex 4), have direct virucidal activity against SARS-CoV-2. Subsequent in vitro testing suggests that complex 4 is the more stable and effective complex and demonstrates that both 2 and 4 have low toxicity in Vero E6 and Calu-3 cells. The results presented here highlight the potential application of organometallic complexes as antivirals and support further investigation into their activity.


Subject(s)
Antiviral Agents/pharmacology , Organometallic Compounds/pharmacology , SARS-CoV-2/drug effects , Animals , Antiviral Agents/chemistry , COVID-19/virology , Cell Line , Cell Survival/drug effects , Chlorocebus aethiops , Dose-Response Relationship, Drug , Humans , Molecular Structure , Organometallic Compounds/chemistry , SARS-CoV-2/physiology , Vero Cells , Virus Replication/drug effects
5.
Viruses ; 13(4)2021 04 09.
Article in English | MEDLINE | ID: covidwho-1178430

ABSTRACT

Photodynamic inactivation of pathogenic microorganisms can be successfully used to eradicate pathogens in localized lesions, infected liquid media, and on various surfaces. This technique utilizes the photosensitizer (PS), light, and molecular oxygen to produce reactive oxygen species that kill pathogens. Here, we used the PS, water soluble octakis(cholinyl)zinc phthalocyanine (Zn-PcChol8+), to inactivate an initial 4.75-5.00 IgTCID50/mL titer of SARS-CoV-2, thereby preventing viral infection when tested in Vero E6 cell cultures. Zn-PcChol8+ in a minimally studied concentration, 1 µM and LED 3.75 J/cm2, completely destroyed the infectivity of SARS-CoV-2. To detect possible PS binding sites on the envelope of SARS-CoV-2, we analyzed electrostatic potential and simulated binding of Zn-PcChol8+ to the spike protein of this coronavirus by means of Brownian dynamics software, ProKSim (Protein Kinetics Simulator). Most of the Zn-PcChol8+ molecules formed clusters at the upper half of the stalk within a vast area of negative electrostatic potential. Positioning of the PS on the surface of the spike protein at a distance of no more than 10 nm from the viral membrane may be favorable for the oxidative damage. The high sensitivity of SARS-CoV-2 to photodynamic inactivation by Zn-PcChol8+ is discussed with respect to the application of this PS to control the spread of COVID-19.


Subject(s)
Indoles/pharmacology , Organometallic Compounds/pharmacology , Photosensitizing Agents/pharmacology , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/chemistry , Virus Inactivation/drug effects , Animals , COVID-19/prevention & control , Chlorocebus aethiops , Indoles/chemistry , Isoindoles , Light , Molecular Dynamics Simulation , Organometallic Compounds/chemistry , Photosensitizing Agents/chemistry , Vero Cells , Zinc Compounds
6.
ACS Appl Mater Interfaces ; 13(1): 312-323, 2021 Jan 13.
Article in English | MEDLINE | ID: covidwho-997781

ABSTRACT

In this study, we present a modulated synthesis nanocrystalline defective UiO-66 metal-organic framework as a potential chloroquine diphosphate (CQ) delivery system. Increasing the concentration of hydrochloric acid during the modulated synthesis resulted in a considerable increase of pore volume, which enhanced the CQ loading in CQ@UiO-66 composites. Drug release tests for CQ@UiO-66 composites have confirmed prolonged CQ release in comparison with pure CQ. In vivo tests on a Danio reiro model organism have revealed that CQ released from CQ@UiO-66 25% showed lower toxicity and fewer cardiotoxic effects manifested by cardiac malformations and arrhythmia in comparison to analogous doses of CQ. Cytotoxicity tests proved that the CQ loaded on the defective UiO-66 cargo resulted in increased viability of cardiac cells (H9C2) as compared to incubation with pure CQ. The experimental results presented here may be a step forward in the context of reducing the cardiotoxicity CQ.


Subject(s)
Chloroquine/analogs & derivatives , Heart Diseases/drug therapy , Metal-Organic Frameworks/pharmacology , Nanoparticles/chemistry , Animals , Chloroquine/adverse effects , Chloroquine/chemistry , Chloroquine/pharmacology , Disease Models, Animal , Drug Delivery Systems/adverse effects , Drug Liberation/drug effects , HEK293 Cells , Heart Diseases/chemically induced , Heart Diseases/pathology , Humans , Hydrochloric Acid/pharmacology , Metal-Organic Frameworks/chemistry , Organometallic Compounds/chemistry , Organometallic Compounds/pharmacology , Phthalic Acids/chemistry , Phthalic Acids/pharmacology , Zebrafish/genetics
7.
Chemistry ; 26(66): 15140-15144, 2020 Nov 26.
Article in English | MEDLINE | ID: covidwho-754877

ABSTRACT

Gold complexes have a long tradition in medicine and for many examples antirheumatic, anticancer or anti-infective effects have been confirmed. Herein, we evaluated the lead compound Auranofin and five selected gold organometallics as inhibitors of two relevant drug targets of severe acute respiratory syndrome coronaviruses (SARS-CoV). The gold metallodrugs were effective inhibitors of the interaction of the SARS-CoV-2 spike protein with the angiotensin converting enzyme 2 (ACE2) host receptor and might thus interfere with the viral entry process. The gold metallodrugs were also efficient inhibitors of the papain-like protease (PLpro) of SARS-CoV-1 and SARS-CoV-2, which is a key enzyme in the viral replication. Regarding PLpro from SARS-CoV-2, the here reported inhibitors are among the very first experimentally confirmed examples with activity against this target enzyme. Importantly, the activity of the complexes against both PLpro enzymes correlated with the ability of the inhibitors to remove zinc ions from the labile zinc center of the enzyme. Taken together, the results of this pilot study suggest further evaluation of gold complexes as SARS-CoV antiviral drugs.


Subject(s)
Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Auranofin/pharmacology , COVID-19/drug therapy , Coronavirus 3C Proteases/antagonists & inhibitors , Gold/chemistry , Organometallic Compounds/pharmacology , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/pharmacology , Auranofin/chemistry , COVID-19/virology , Coronavirus 3C Proteases/metabolism , Gold/pharmacology , Humans , Molecular Targeted Therapy , Organometallic Compounds/chemistry , SARS-CoV-2/enzymology , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism
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