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1.
Molecules ; 27(1)2022 Jan 02.
Article in English | MEDLINE | ID: covidwho-1686893

ABSTRACT

Hypercytokinemia, or cytokine storm, is one of the severe complications of viral and bacterial infections, involving the release of abnormal amounts of cytokines, resulting in a massive inflammatory response. Cytokine storm is associated with COVID-19 and sepsis high mortality rate by developing epithelial dysfunction and coagulopathy, leading to thromboembolism and multiple organ dysfunction syndrome. Anticoagulant therapy is an important tactic to prevent thrombosis in sepsis and COVID-19, but recent data show the incompatibility of modern direct oral anticoagulants and antiviral agents. It seems relevant to develop dual-action drugs with antiviral and anticoagulant properties. At the same time, it was shown that azolo[1,5-a]pyrimidines are heterocycles with a broad spectrum of antiviral activity. We have synthesized a new family of azolo[1,5-a]pyrimidines and their condensed polycyclic analogs by cyclocondensation reactions and direct CH-functionalization and studied their anticoagulant properties. Five compounds among 1,2,4-triazolo[1,5-a]pyrimidin-7-ones and 5-alkyl-1,3,4-thiadiazolo[3,2-a]purin-8-ones demonstrated higher anticoagulant activity than the reference drug, dabigatran etexilate. Antithrombin activity of most active compounds was confirmed using lipopolysaccharide (LPS)-treated blood to mimic the conditions of cytokine release syndrome. The studied compounds affected only the thrombin time value, reliably increasing it 6.5-15.2 times as compared to LPS-treated blood.


Subject(s)
Anticoagulants/pharmacology , Azo Compounds/chemistry , Blood Coagulation/drug effects , Hemorrhage/drug therapy , Pyrimidines/chemistry , Animals , Anticoagulants/chemistry , Hemorrhage/chemically induced , Lipopolysaccharides/toxicity , Male , Rabbits , Rats
2.
Cell Chem Biol ; 29(2): 215-225.e5, 2022 02 17.
Article in English | MEDLINE | ID: covidwho-1664751

ABSTRACT

Coagulation cofactors profoundly regulate hemostasis and are appealing targets for anticoagulants. However, targeting such proteins has been challenging because they lack an active site. To address this, we isolate an RNA aptamer termed T18.3 that binds to both factor V (FV) and FVa with nanomolar affinity and demonstrates clinically relevant anticoagulant activity in both plasma and whole blood. The aptamer also shows synergy with low molecular weight heparin and delivers potent anticoagulation in plasma collected from patients with coronavirus disease 2019 (COVID-19). Moreover, the aptamer's anticoagulant activity can be rapidly and efficiently reversed using protamine sulfate, which potentially allows fine-tuning of aptamer's activity post-administration. We further show that the aptamer achieves its anticoagulant activity by abrogating FV/FVa interactions with phospholipid membranes. Our success in generating an anticoagulant aptamer targeting FV/Va demonstrates the feasibility of using cofactor-binding aptamers as therapeutic protein inhibitors and reveals an unconventional working mechanism of an aptamer by interrupting protein-membrane interactions.


Subject(s)
Anticoagulants/pharmacology , Aptamers, Nucleotide/pharmacology , Blood Coagulation/drug effects , Factor V/antagonists & inhibitors , Factor Va/antagonists & inhibitors , Amino Acid Sequence , Anticoagulants/chemistry , Anticoagulants/metabolism , Aptamers, Nucleotide/chemistry , Aptamers, Nucleotide/metabolism , Base Pairing , Binding Sites , COVID-19/blood , COVID-19/drug therapy , Cell Membrane/chemistry , Cell Membrane/metabolism , Factor V/chemistry , Factor V/genetics , Factor V/metabolism , Factor Va/chemistry , Factor Va/genetics , Factor Va/metabolism , Heparin, Low-Molecular-Weight/chemistry , Heparin, Low-Molecular-Weight/metabolism , Humans , Immune Sera/chemistry , Immune Sera/metabolism , Models, Molecular , Nucleic Acid Conformation , Protamines , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , SARS-CoV-2/growth & development , SARS-CoV-2/pathogenicity , SELEX Aptamer Technique , Substrate Specificity
3.
Toxins (Basel) ; 13(12)2021 12 20.
Article in English | MEDLINE | ID: covidwho-1591291

ABSTRACT

Hemostatic disorders are caused either by platelet-related dysfunctions, defective blood coagulation, or by a combination of both, leading to an increased susceptibility to cardiovascular diseases (CVD) and other related illnesses. The unique specificity of anticoagulants from hematophagous arthropods, such as ticks, suggests that tick saliva holds great promise for discovering new treatments for these life-threatening diseases. In this study, we combined in silico and in vitro analyses to characterize the first recombinant serpin, herein called Dromaserpin, from the sialotranscriptome of the Hyalomma dromedarii tick. Our in silico data described Dromaserpin as a secreted protein of ~43 kDa with high similarities to previously characterized inhibitory serpins. The recombinant protein (rDromaserpin) was obtained as a well-structured monomer, which was tested using global blood coagulation and platelet aggregation assays. With this approach, we confirmed rDromaserpin anticoagulant activity as it significantly delayed plasma clotting in activated partial thromboplastin time and thrombin time assays. The profiling of proteolytic activity shows its capacity to inhibit thrombin in the micromolar range (0.2 to 1 µM) and in the presence of heparin this inhibition was clearly increased. It was also able to inhibit Kallikrein, FXIa and slightly FXIIa, with no significant effect on other factors. In addition, the rDromaserpin inhibited thrombin-induced platelet aggregation. Taken together, our data suggest that rDromaserpin deserves to be further investigated as a potential candidate for developing therapeutic compounds targeting disorders related to blood clotting and/or platelet aggregation.


Subject(s)
Blood Coagulation/drug effects , Ixodidae/metabolism , Serpins/chemistry , Serpins/pharmacology , Amino Acid Sequence , Animals , Anticoagulants/chemistry , Anticoagulants/metabolism , Computer Simulation , Models, Molecular , Phylogeny , Protein Conformation , Serpins/metabolism
4.
Nutrients ; 13(12)2021 Nov 29.
Article in English | MEDLINE | ID: covidwho-1542693

ABSTRACT

Bromelain is a major sulfhydryl proteolytic enzyme found in pineapple plants, having multiple activities in many areas of medicine. Due to its low toxicity, high efficiency, high availability, and relative simplicity of acquisition, it is the object of inexhaustible interest of scientists. This review summarizes scientific reports concerning the possible application of bromelain in treating cardiovascular diseases, blood coagulation and fibrinolysis disorders, infectious diseases, inflammation-associated diseases, and many types of cancer. However, for the proper application of such multi-action activities of bromelain, further exploration of the mechanism of its action is needed. It is supposed that the anti-viral, anti-inflammatory, cardioprotective and anti-coagulatory activity of bromelain may become a complementary therapy for COVID-19 and post-COVID-19 patients. During the irrepressible spread of novel variants of the SARS-CoV-2 virus, such beneficial properties of this biomolecule might help prevent escalation and the progression of the COVID-19 disease.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Anticoagulants/therapeutic use , Blood Coagulation Disorders/drug therapy , Bromelains/therapeutic use , COVID-19/drug therapy , Cardiotonic Agents/therapeutic use , Cardiovascular Diseases/drug therapy , Neoplasms/drug therapy , Plant Proteins/therapeutic use , SARS-CoV-2 , Ananas/enzymology , Anti-Inflammatory Agents/chemistry , Anticoagulants/chemistry , Bromelains/chemistry , Cardiotonic Agents/chemistry , Fibrinolysis/drug effects , Humans , Plant Proteins/chemistry
5.
Int J Mol Sci ; 22(21)2021 Nov 07.
Article in English | MEDLINE | ID: covidwho-1512380

ABSTRACT

Heparin and its derivatives are saving thousands of human lives annually, by successfully preventing and treating thromboembolic events. Although the mode of action during anticoagulation is well studied, their influence on cell behavior is not fully understood as is the risk of bleeding and other side effects. New applications in regenerative medicine have evolved supporting production of cell-based therapeutics or as a substrate for creating functionalized matrices in biotechnology. The currently resurgent interest in heparins is related to the expected combined anti-inflammatory, anti-thrombotic and anti-viral action against COVID-19. Based on a concise summary of key biochemical and clinical data, this review summarizes the impact for manufacturing and application of cell therapeutics and highlights the need for discriminating the different heparins.


Subject(s)
Anticoagulants/chemistry , Cell- and Tissue-Based Therapy/methods , Heparin/analogs & derivatives , Anticoagulants/adverse effects , Anticoagulants/therapeutic use , Biocompatible Materials/chemistry , Biocompatible Materials/therapeutic use , Cell Adhesion , Hemorrhage/etiology , Heparin/adverse effects , Heparin/therapeutic use , Humans , Mesenchymal Stem Cells/cytology , Mesenchymal Stem Cells/metabolism , Regenerative Medicine , Thromboembolism/drug therapy
6.
Molecules ; 26(9)2021 Apr 29.
Article in English | MEDLINE | ID: covidwho-1217102

ABSTRACT

Hemostasis disorders play an important role in the pathogenesis, clinical manifestations, and outcome of COVID-19. First of all, the hemostasis system suffers due to a complicated and severe course of COVID-19. A significant number of COVID-19 patients develop signs of hypercoagulability, thrombocytopenia, and hyperfibrinolysis. Patients with severe COVID-19 have a tendency toward thrombotic complications in the venous and arterial systems, which is the leading cause of death in this disease. Despite the success achieved in the treatment of SARS-CoV-2, the search for new effective anticoagulants, thrombolytics, and fibrinolytics, as well as their optimal dose strategies, continues to be relevant. The wide therapeutic potential of seaweed sulfated polysaccharides (PSs), including anticoagulant, thrombolytic, and fibrinolytic activities, opens up new possibilities for their study in experimental and clinical trials. These natural compounds can be important complementary drugs for the recovery from hemostasis disorders due to their natural origin, safety, and low cost compared to synthetic drugs. In this review, the authors analyze possible pathophysiological mechanisms involved in the hemostasis disorders observed in the pathological progression of COVID-19, and also focus the attention of researchers on seaweed PSs as potential drugs aimed to correction these disorders in COVID-19 patients. Modern literature data on the anticoagulant, antithrombotic, and fibrinolytic activities of seaweed PSs are presented, depending on their structural features (content and position of sulfate groups on the main chain of PSs, molecular weight, monosaccharide composition and type of glycosidic bonds, the degree of PS chain branching, etc.). The mechanisms of PS action on the hemostasis system and the issues of oral bioavailability of PSs, important for their clinical use as oral anticoagulant and antithrombotic agents, are considered. The combination of the anticoagulant, thrombolytic, and fibrinolytic properties, along with low toxicity and relative cheapness of production, open up prospects for the clinical use of PSs as alternative sources of new anticoagulant and antithrombotic compounds. However, further investigation and clinical trials are needed to confirm their efficacy.


Subject(s)
Anticoagulants/pharmacology , COVID-19/complications , Hemostasis/drug effects , Polysaccharides/pharmacology , Seaweed , Sulfates/pharmacology , Thrombosis/complications , Animals , Anticoagulants/chemistry , Anticoagulants/pharmacokinetics , Anticoagulants/therapeutic use , COVID-19/blood , COVID-19/drug therapy , Drug Discovery , Humans , Polysaccharides/chemistry , Polysaccharides/pharmacokinetics , Polysaccharides/therapeutic use , Seaweed/chemistry , Sulfates/chemistry , Sulfates/pharmacokinetics , Sulfates/therapeutic use , Thrombosis/blood , Thrombosis/drug therapy
7.
Carbohydr Res ; 505: 108326, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1213065

ABSTRACT

The viral infection caused by SARS-CoV-2 has increased the mortality rate and engaged several adverse effects on the affected individuals. Currently available antiviral drugs have found to be unsuccessful in the treatment of COVID-19 patients. The demand for efficient antiviral drugs has created a huge burden on physicians and health workers. Plasma therapy seems to be less accomplishable due to insufficient donors to donate plasma and low recovery rate from viral infection. Repurposing of antivirals has been evolved as a suitable strategy in the current treatment and preventive measures. The concept of drug repurposing represents new experimental approaches for effective therapeutic benefits. Besides, SARS-CoV-2 exhibits several complications such as lung damage, blood clot formation, respiratory illness and organ failures in most of the patients. Based on the accumulation of data, sulfated marine polysaccharides have exerted successful inhibition of virus entry, attachment and replication with known or unknown possible mechanisms against deadly animal and human viruses so far. Since the virus entry into the host cells is the key process, the prevention of such entry mechanism makes any antiviral strategy effective. Enveloped viruses are more sensitive to polyanions than non-enveloped viruses. Besides, the viral infection caused by RNA virus types embarks severe oxidative stress in the human body that leads to malfunction of tissues and organs. In this context, polysaccharides play a very significant role in providing shielding effect against the virus due to their polyanionic rich features and a molecular weight that hinders their reactive surface glycoproteins. Significantly the functional groups especially sulfate, sulfate pattern and addition, uronic acids, monosaccharides, glycosidic linkage and high molecular weight have greater influence in the antiviral activity. Moreover, they are very good antioxidants that can reduce the free radical generation and provokes intracellular antioxidant enzymes. Additionally, polysaccharides enable a host-virus immune response, activate phagocytosis and stimulate interferon systems. Therefore, polysaccharides can be used as candidate drugs, adjuvants in vaccines or combination with other antivirals, antioxidants and immune-activating nutritional supplements and antiviral materials in healthcare products to prevent SARS-CoV-2 infection.


Subject(s)
Anticoagulants/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Immunologic Factors/therapeutic use , Polysaccharides/therapeutic use , Pulmonary Embolism/drug therapy , Respiratory Insufficiency/drug therapy , Anticoagulants/chemistry , Anticoagulants/isolation & purification , Antiviral Agents/chemistry , Antiviral Agents/isolation & purification , Blood Platelets/drug effects , Blood Platelets/pathology , Blood Platelets/virology , COVID-19/complications , COVID-19/diagnosis , COVID-19/virology , Humans , Immunologic Factors/chemistry , Immunologic Factors/isolation & purification , Lung/blood supply , Lung/drug effects , Lung/pathology , Lung/virology , Phaeophyta/chemistry , Polysaccharides/chemistry , Polysaccharides/isolation & purification , Pulmonary Embolism/complications , Pulmonary Embolism/diagnosis , Pulmonary Embolism/virology , Respiratory Insufficiency/complications , Respiratory Insufficiency/diagnosis , Respiratory Insufficiency/virology , Rhodophyta/chemistry , SARS-CoV-2/drug effects , SARS-CoV-2/pathogenicity , Sulfuric Acid Esters/chemistry , Virus Attachment/drug effects , Virus Internalization/drug effects
8.
Blood Purif ; 50(1): 28-34, 2021.
Article in English | MEDLINE | ID: covidwho-624949

ABSTRACT

In April 2020, the US Food and Drug Administration granted emergency use authorization for certain medical devices to be used in patients with coronavirus disease 2019 (CO-VID-19). This included extracorporeal blood purification devices. This narrative review will give a brief overview regarding some of the extracorporeal devices that could be used to treat COVID-19 patients, including the Seraph® 100 Microbind® Affinity Blood Filter, produced by ExThera Medical (Martinez, CA, USA), first licensed in the European Economic Area in 2019. The Seraph® 100 contains ultrahigh molecular weight polyethylene beads with end point-attached heparin and is approved for the reduction of pathogens from the bloodstream either as a single agent or as an adjunct to conventional anti-infective agents. Bacteria, viruses, fungi, and toxins have been shown to bind to the immobilized heparin in a similar way to the interaction with heparan sulfate on the cell surface. This binding is nonreversible and as such, the pathogens are removed from the bloodstream. In this review, we describe the pathophysiological basis and rationale for using heparin for pathogen removal from the blood as well as exploring the technology behind the adaptation of heparin to deprive it of its systemic anticoagulant activity. In addition, we summarize the in vitro data as well as the available preclinical testing and published clinical reports. Finally, we discuss the enormous potential of this technology in an era of increasing antibiotic resistance and high mortality associated with sepsis and consider the application of this as a possible treatment option for COVID-19.


Subject(s)
Anticoagulants/chemistry , Bacterial Infections/therapy , COVID-19/therapy , Hemoperfusion/methods , Heparin/chemistry , SARS-CoV-2/isolation & purification , Bacteria/isolation & purification , Bacterial Infections/blood , Binding Sites , COVID-19/blood , Humans
9.
Molecules ; 25(11)2020 May 29.
Article in English | MEDLINE | ID: covidwho-436971

ABSTRACT

The coronavirus disease, COVID-19, caused by the novel coronavirus SARS-CoV-2, which first emerged in Wuhan, China and was made known to the World in December 2019 turned into a pandemic causing more than 126,124 deaths worldwide up to April 16th, 2020. It has 79.5% sequence identity with SARS-CoV-1 and the same strategy for host cell invasion through the ACE-2 surface protein. Since the development of novel drugs is a long-lasting process, researchers look for effective substances among drugs already approved or developed for other purposes. The 3D structure of the SARS-CoV-2 main protease was compared with the 3D structures of seven proteases, which are drug targets, and docking analysis to the SARS-CoV-2 protease structure of thirty four approved and on-trial protease inhibitors was performed. Increased 3D structural similarity between the SARS-CoV-2 main protease, the HCV protease and α-thrombin was found. According to docking analysis the most promising results were found for HCV protease, DPP-4, α-thrombin and coagulation Factor Xa known inhibitors, with several of them exhibiting estimated free binding energy lower than -8.00 kcal/mol and better prediction results than reference compounds. Since some of the compounds are well-tolerated drugs, the promising in silico results may warrant further evaluation for viral anticipation. DPP-4 inhibitors with anti-viral action may be more useful for infected patients with diabetes, while anti-coagulant treatment is proposed in severe SARS-CoV-2 induced pneumonia.


Subject(s)
Anticoagulants/chemistry , Antiviral Agents/chemistry , Betacoronavirus/drug effects , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Protease Inhibitors/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Amino Acid Sequence , Anticoagulants/pharmacology , Antiviral Agents/pharmacology , Betacoronavirus/chemistry , Betacoronavirus/enzymology , Betacoronavirus/genetics , Binding Sites , COVID-19 , Coronavirus 3C Proteases , Coronavirus Infections/drug therapy , Cysteine Endopeptidases/chemistry , Cysteine Endopeptidases/genetics , Cysteine Endopeptidases/metabolism , Dipeptidyl Peptidase 4/chemistry , Dipeptidyl Peptidase 4/genetics , Dipeptidyl Peptidase 4/metabolism , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Factor Xa/chemistry , Factor Xa/genetics , Factor Xa/metabolism , Hepacivirus/chemistry , Hepacivirus/enzymology , Hepacivirus/genetics , Humans , Molecular Docking Simulation , Pandemics , Pneumonia, Viral/drug therapy , Protease Inhibitors/pharmacology , Protein Binding , Protein Conformation , Protein Interaction Domains and Motifs , SARS-CoV-2 , Sequence Alignment , Structural Homology, Protein , Substrate Specificity , Thermodynamics , Thrombin/antagonists & inhibitors , Thrombin/chemistry , Thrombin/genetics , Thrombin/metabolism , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/genetics , Viral Nonstructural Proteins/metabolism
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