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1.
Biomedicines ; 10(7)2022 Jul 18.
Article in English | MEDLINE | ID: covidwho-1938690

ABSTRACT

Diminazene aceturate (DIZE) is a putative angiotensin-converting enzyme 2 (ACE2) activator and angiotensin type 1 receptor antagonist (AT1R). Its simple chemical structure possesses a negatively charged triazene segment that is homologous to the tetrazole of angiotensin receptor blockers (ARB), which explains its AT1R antagonistic activity. Additionally, the activation of ACE2 by DIZE converts the toxic octapeptide angiotensin II (AngII) to the heptapeptides angiotensin 1-7 and alamandine, which promote vasodilation and maintains homeostatic balance. Due to DIZE's protective cardiovascular and pulmonary effects and its ability to target ACE2 (the predominant receptor utilized by severe acute respiratory syndrome coronavirus 2 to enter host cells), it is a promising treatment for coronavirus 2019 (COVID-19). To determine DIZE's ability to inhibit AngII constriction, in vitro isometric tension analysis was conducted on rabbit iliac arteries incubated with DIZE or candesartan and constricted with cumulative doses of AngII. In silico docking and ligand interaction studies were performed to investigate potential interactions between DIZE and other ARBs with AT1R and the spike protein/ACE2 complex. DIZE, similar to the other ARBs investigated, was able to abolish vasoconstriction in response to AngII and exhibited a binding affinity for the spike protein/ACE2 complex (PDB 6LZ6). These results support the potential of DIZE as a treatment for COVID-19.

2.
Viruses ; 14(5)2022 05 11.
Article in English | MEDLINE | ID: covidwho-1869808

ABSTRACT

SARS-CoV-2 is a global challenge due to its ability to mutate into variants that spread more rapidly than the wild-type virus. Because the molecular biology of this virus has been studied in such great detail, it represents an archetypal paradigm for research into new antiviral drug therapies. The rapid evolution of SARS-CoV-2 in the human population is driven, in part, by mutations in the receptor-binding domain (RBD) of the spike (S-) protein, some of which enable tighter binding to angiotensin-converting enzyme (ACE2). More stable RBD-ACE2 association is coupled with accelerated hydrolysis of furin and 3CLpro cleavage sites that augment infection. Non-RBD and non-interfacial mutations assist the S-protein in adopting thermodynamically favorable conformations for stronger binding. The driving forces of key mutations for Alpha, Beta, Gamma, Delta, Kappa, Lambda and Omicron variants, which stabilize the RBD-ACE2 complex, are investigated by free-energy computational approaches, as well as equilibrium and steered molecular dynamic simulations. Considered also are the structural hydropathy traits of the residues in the interface between SARS-CoV-2 RBD and ACE2 protein. Salt bridges and π-π interactions are critical forces that create stronger complexes between the RBD and ACE2. The trend of mutations is the replacement of non-polar hydrophobic interactions with polar hydrophilic interactions, which enhance binding of RBD with ACE2. However, this is not always the case, as conformational landscapes also contribute to a stronger binding. Arginine, the most polar and hydrophilic among the natural amino acids, is the most aggressive mutant amino acid for stronger binding. Arginine blockers, such as traditional sartans that bear anionic tetrazoles and carboxylates, may be ideal candidate drugs for retarding viral infection by weakening S-protein RBD binding to ACE2 and discouraging hydrolysis of cleavage sites. Based on our computational results it is suggested that a new generation of "supersartans", called "bisartans", bearing two anionic biphenyl-tetrazole pharmacophores, are superior to carboxylates in terms of their interactions with viral targets, suggesting their potential as drugs in the treatment of COVID-19. In Brief: This in silico study reviews our understanding of molecular driving forces that trigger mutations in the SARS-CoV-2 virus. It also reports further studies on a new class of "supersartans" referred to herein as "bisartans", bearing two anionic biphenyltetrazole moieties that show potential in models for blocking critical amino acids of mutants, such as arginine, in the Delta variant. Bisartans may also act at other targets essential for viral infection and replication (i.e., ACE2, furin cleavage site and 3CLpro), rendering them potential new drugs for additional experimentation and translation to human clinical trials.


Subject(s)
COVID-19 , SARS-CoV-2 , Angiotensin-Converting Enzyme 2/genetics , Arginine/genetics , COVID-19/drug therapy , Furin/genetics , Humans , Membrane Glycoproteins/metabolism , Mutation , Receptors, Virus/metabolism , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Viral Envelope Proteins/genetics
3.
Comput Struct Biotechnol J ; 20: 2091-2111, 2022.
Article in English | MEDLINE | ID: covidwho-1778074

ABSTRACT

The discovery and facile synthesis of a new class of sartan-like arterial antihypertensive drugs (angiotensin receptor blockers [ARBs]), subsequently referred to as "bisartans" is reported. In vivo results and complementary molecular modelling presented in this communication indicate bisartans may be beneficial for the treatment of not only heart disease, diabetes, renal dysfunction, and related illnesses, but possibly COVID-19. Bisartans are novel bis-alkylated imidazole sartan derivatives bearing dual symmetric anionic biphenyl tetrazole moieties. In silico docking and molecular dynamics studies revealed bisartans exhibited higher binding affinities for the ACE2/spike protein complex (PDB 6LZG) compared to all other known sartans. They also underwent stable docking to the Zn2 + domain of the ACE2 catalytic site as well as the critical interfacial region between ACE2 and the SARS-CoV-2 receptor binding domain. Additionally, semi-stable docking of bisartans at the arginine-rich furin-cleavage site of the SARS-CoV-2 spike protein (residues 681-686) required for virus entry into host cells, suggest bisartans may inhibit furin action thereby retarding viral entry into host cells. Bisartan tetrazole groups surpass nitrile, the pharmacophoric "warhead" of PF-07321332, in its ability to disrupt the cysteine charge relay system of 3CLpro. However, despite the apparent targeting of multifunctional sites, bisartans do not inhibit SARS-CoV-2 infection in bioassays as effectively as PF-07321332 (Paxlovid).

4.
EPMA J ; 12(2): 155-176, 2021 Jun.
Article in English | MEDLINE | ID: covidwho-1300538

ABSTRACT

Cost-efficacy of currently applied treatments is an issue in overall cancer management challenging healthcare and causing tremendous economic burden to societies around the world. Consequently, complex treatment models presenting concepts of predictive diagnostics followed by targeted prevention and treatments tailored to the personal patient profiles earn global appreciation as benefiting the patient, healthcare economy, and the society at large. In this context, application of flavonoids as a spectrum of compounds and their nano-technologically created derivatives is extensively under consideration, due to their multi-faceted anti-cancer effects applicable to the overall cost-effective cancer management, primary, secondary, and even tertiary prevention. This article analyzes most recently updated data focused on the potent capacity of flavonoids to promote anti-cancer therapeutic effects and interprets all the collected research achievements in the frame-work of predictive, preventive, and personalized (3P) medicine. Main pillars considered are: - Predictable anti-neoplastic, immune-modulating, drug-sensitizing effects; - Targeted molecular pathways to improve therapeutic outcomes by increasing sensitivity of cancer cells and reversing their resistance towards currently applied therapeutic modalities.

5.
Biomolecules ; 11(7)2021 07 03.
Article in English | MEDLINE | ID: covidwho-1295754

ABSTRACT

Angiotensin II (Ang II) may contain a charge relay system (CRS) involving Tyr/His/carboxylate, which creates a tyrosinate anion for receptor activation. Energy calculations were carried out to determine the preferred geometry for the CRS in the presence and absence of the Arg guanidino group occupying position 2 of Ang II. These findings suggest that Tyr is preferred over His for bearing the negative charge and that the CRS is stabilized by the guanidino group. Recent crystallography studies provided details of the binding of nonpeptide angiotensin receptor blockers (ARBs) to the Ang II type 1 (AT1) receptor, and these insights were applied to Ang II. A model of binding and receptor activation that explains the surmountable and insurmountable effects of Ang II analogues sarmesin and sarilesin, respectively, was developed and enabled the discovery of a new generation of ARBs called bisartans. Finally, we determined the ability of the bisartan BV6(TFA) to act as a potential ARB, demonstrating similar effects to candesartan, by reducing vasoconstriction of rabbit iliac arteries in response to cumulative doses of Ang II. Recent clinical studies have shown that Ang II receptor blockers have protective effects in hypertensive patients infected with SARS-CoV-2. Therefore, the usage of ARBS to block the AT1 receptor preventing the binding of toxic angiotensin implicated in the storm of cytokines in SARS-CoV-2 is a target treatment and opens new avenues for disease therapy.


Subject(s)
Angiotensin II/metabolism , Angiotensin Receptor Antagonists/chemistry , Angiotensin Receptor Antagonists/pharmacology , COVID-19/drug therapy , Drug Discovery , Receptor, Angiotensin, Type 1/metabolism , Angiotensin II/analogs & derivatives , Animals , COVID-19/metabolism , Crystallography, X-Ray , Humans , Hypertension/drug therapy , Hypertension/metabolism , Male , Models, Molecular , Rabbits , Receptor, Angiotensin, Type 1/chemistry , Vasoconstriction/drug effects
6.
Int J Mol Sci ; 22(3)2021 Jan 20.
Article in English | MEDLINE | ID: covidwho-1067752

ABSTRACT

The occurrence of the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), responsible for coronavirus disease 2019 (COVD-19), represents a catastrophic threat to global health. Protruding from the viral surface is a densely glycosylated spike (S) protein, which engages angiotensin-converting enzyme 2 (ACE2) to mediate host cell entry. However, studies have reported viral susceptibility in intra- and extrapulmonary immune and non-immune cells lacking ACE2, suggesting that the S protein may exploit additional receptors for infection. Studies have demonstrated interactions between S protein and innate immune system, including C-lectin type receptors (CLR), toll-like receptors (TLR) and neuropilin-1 (NRP1), and the non-immune receptor glucose regulated protein 78 (GRP78). Recognition of carbohydrate moieties clustered on the surface of the S protein may drive receptor-dependent internalization, accentuate severe immunopathological inflammation, and allow for systemic spread of infection, independent of ACE2. Furthermore, targeting TLRs, CLRs, and other receptors (Ezrin and dipeptidyl peptidase-4) that do not directly engage SARS-CoV-2 S protein, but may contribute to augmented anti-viral immunity and viral clearance, may represent therapeutic targets against COVID-19.


Subject(s)
COVID-19/metabolism , COVID-19/pathology , SARS-CoV-2/physiology , Virus Internalization , Angiotensin-Converting Enzyme 2/immunology , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/immunology , Disease Progression , Heat-Shock Proteins/immunology , Heat-Shock Proteins/metabolism , Host-Pathogen Interactions , Humans , Lectins, C-Type/immunology , Lectins, C-Type/metabolism , Neuropilin-1/immunology , Neuropilin-1/metabolism , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism , Toll-Like Receptors/immunology , Toll-Like Receptors/metabolism
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