ACE2 Receptor Research Articles

Computational Evidence for Bisartan Arginine Blockers as Next-Generation Pan-Antiviral Therapeutics Targeting SARS-CoV-2, Influenza, and Respiratory Syncytial Viruses

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza, and respiratory syncytial virus (RSV) are significant global health threats. The need for low-cost, easily synthesized oral drugs for rapid deployment during outbreaks is crucial. Broad-spectrum therapeutics, or pan-antivirals, are designed to target multiple viral pathogens simultaneously by focusing on shared molecular features, such as common metal cofactors or conserved residues in viral catalytic domains. This study introduces a new generation of potent sartans, known as bisartans, engineered in our laboratories with negative charges from carboxylate or tetrazolate groups. These anionic tetrazoles interact strongly with cationic arginine residues or metal cations (e.g., Zn2+) within viral and host target sites, including the SARS-CoV-2 ACE2 receptor, influenza H1N1 neuraminidases, and the RSV fusion protein. Using virtual ligand docking and molecular dynamics, we investigated how bisartans and their analogs bind to these viral receptors, potentially blocking infection through a pan-antiviral mechanism. Bisartan, ACC519TT, demonstrated stable and high-affinity docking to key catalytic domains of the SARS-CoV-2 NSP3, H1N1 neuraminidase, and RSV fusion protein, outperforming FDA-approved drugs like Paxlovid and oseltamivir. It also showed strong binding to the arginine-rich furin cleavage sites S1/S2 and S2′, suggesting interference with SARS-CoV-2’s spike protein cleavage. The results highlight the potential of tetrazole-based bisartans as promising candidates for developing broad-spectrum antiviral therapies.

Dual Assay Validation of Rosmarinus officinalis Extract as an Inhibitor of SARS-CoV-2 Spike Protein: Combining Pseudovirus Testing, Yeast Two-Hybrid, and UPLC-Q Exactive Orbitrap-MS Profiling.

This study evaluates the effectiveness of Traditional Chinese Medicine (TCM) extracts in blocking the interaction between the SARS-CoV-2 Spike protein and human ACE2 receptor, utilizing a dual-method approach to explore the antiviral potential of natural compounds. This work aims to evaluate the capability of TCM extracts in inhibiting the SARS-CoV-2 Spike protein and ACE2 receptor interaction using advanced biochemical assays. A dual-method screening approach was utilized, beginning with a pseudovirus assay to assess the inhibition capabilities of TCM extracts invitro, followed by a split-ubiquitin yeast two-hybrid (Y2H) system to validate interactions in live cells. Active compounds were characterized and quantified using UPLC-Q-Exactive-Orbitrap-MS. Among the 91 TCM extracts tested, Rosmarinus officinalis exhibited the most potent inhibition in both pseudovirus and Y2H assays, significantly reducing viral entry and disrupting the Spike-ACE2 interaction. Comprehensive chemical profiling via UPLC-Q-Exactive-Orbitrap-MS identified 132 compounds, including phenolics, flavonoids, and terpenoids. This research validates the use of TCM extracts in viral inhibition strategies, demonstrating the utility of integrating traditional remedies with modern scientific approaches to discover new therapeutic agents.

AI Promoted Virtual Screening, Structure-Based Hit Optimization, and Synthesis of Novel COVID-19 S-RBD Domain Inhibitors.

Coronavirus disease 2019 (COVID-19) is caused by a new, highly pathogenic severe-acute-respiratory syndrome coronavirus 2 (SARS-CoV-2) that infects human cells through its transmembrane spike (S) glycoprotein. The receptor-binding domain (RBD) of the S protein interacts with the angiotensin-converting enzyme II (ACE2) receptor of the host cells. Therefore, pharmacological targeting of this interaction might prevent infection or spread of the virus. Here, we performed a virtual screening to identify small molecules that block S-ACE2 interaction. Large compound libraries were filtered for drug-like properties, promiscuity and protein-protein interaction-targeting ability based on their ADME-Tox descriptors and also to exclude pan-assay interfering compounds. A properly designed AI-based virtual screening pipeline was applied to the remaining compounds, comprising approximately 10% of the starting data sets, searching for molecules that could bind to the RBD of the S protein. All molecules were sorted according to their screening score, grouped based on their structure and postfiltered for possible interaction patterns with the ACE2 receptor, yielding 31 hits. These hit molecules were further tested for their inhibitory effect on Spike RBD/ACE2 (19-615) interaction. Six compounds inhibited the S-ACE2 interaction in a dose-dependent manner while two of them also prevented infection of human cells from a pseudotyped virus whose entry is mediated by the S protein of SARS-CoV-2. Of the two compounds, the benzimidazole derivative CKP-22 protected Vero E6 cells from infection with SARS-CoV-2, as well. Subsequent, hit-to-lead optimization of CKP-22 was effected through the synthesis of 29 new derivatives of which compound CKP-25 suppressed the Spike RBD/ACE2 (19-615) interaction, reduced the cytopathic effect of SARS-CoV-2 in Vero E6 cells (IC50 = 3.5 μM) and reduced the viral load in cell culture supernatants. Early in vitro ADME-Tox studies showed that CKP-25 does not possess biodegradation or liver metabolism issues, while isozyme-specific CYP450 experiments revealed that CKP-25 was a weak inhibitor of the CYP450 system. Moreover, CKP-25 does not elicit mutagenic effect on Escherichia coli WP2 uvrA strain. Thus, CKP-25 is considered a lead compound against COVID-19 infection.

Super broad and protective nanobodies against Sarbecoviruses including SARS-CoV-1 and the divergent SARS-CoV-2 subvariant KP.3.1.1.

The ongoing evolution and immune escape of SARS-CoV-2, alongside the potential threat of SARS-CoV-1 and other sarbecoviruses, underscore the urgent need for effective strategies against their infection and transmission. This study highlights the discovery of nanobodies from immunized alpacas, which demonstrate exceptionally broad and potent neutralizing capabilities against the recently emerged and more divergent SARS-CoV-2 Omicron subvariants including JD.1.1, JN.1, KP.3, KP.3.1.1, as well as SARS-CoV-1 and coronaviruses from bats and pangolins utilizing receptor ACE2. Among these, Tnb04-1 emerges as the most broad and potent, binding to a conserved hydrophobic pocket in the spike's receptor-binding domain, distinct from the ACE2 binding site. This interaction disrupts the formation of a proteinase K-resistant core, crucial for viral-cell fusion. Notably, intranasal administration of Tnb04-1 in Syrian hamsters effectively prevented respiratory infection and transmission of the authentic Omicron XBB.1.5 subvariant. Thus, Thb04-1 holds promise in combating respiratory acquisition and transmission of diverse sarbecoviruses.

Antiviral efficacy of heparan sulfate and enoxaparin sodium against SARS-CoV-2.

As the world transitions from the acute phase of the COVID-19 pandemic caused by SARS-CoV-2, the scientific community continues to explore various therapeutic avenues to control its spread and mitigate its ongoing effects. Among the promising candidates are heparan sulfate (HS) and enoxaparin (EX), which have emerged as potential virus inhibitors. HS, a type of glycosaminoglycan, plays a prominent role in the attachment of the virus to host cells. At the same time, EX, a low-molecular-weight heparin, is being investigated for its ability to disrupt the interaction between the spike protein of SARS-CoV-2 and the ACE2 receptor in human cells. Understanding the mechanisms through which these substances operate could lay the foundation for new strategies in the ongoing management of COVID-19. This study aimed to examine the details of SARS-CoV-2's entry mechanisms and the role of HS in this process. Furthermore, it examines EX's mechanism of action, highlighting how it potentially inhibits SARS-CoV-2. The interactions between HS and the virus, alongside in-vitro and in-silico inhibition studies with HS and EX, are critically analyzed to assess their antiviral efficacy. Additionally, the antiviral activity of sulfated polysaccharides and the potential therapeutic applications of these findings are discussed.

Downregulation of Neuronal Nitric Oxide Synthase (nNOS) within the Paraventricular Nucleus in Ins2Akita-type-1 Diabetic Mice Contributes to Sympatho-excitation

Activation of both renin-angiotensin system (RAS) and the sympathetic system is the primary etiologic event in developing cardiovascular complications in diabetes mellitus (DM). However, the precise mechanisms for sympathetic activation in DM have not been elucidated. Here we attempted to investigate diabetes-linked cardiovascular dysregulation due to angiotensin II (Ang II)-mediated reduction in neuronal nitric oxide (NO) synthase (nNOS) within the paraventricular neuleus (PVN). In the present study, we used Ins2+/-Akita (a spontaneous, insulin-dependent genetic diabetic non-obese murine model) and wild-type (WT) littermates mice as controls. At 14 weeks of age, we found the Akita mice had increased renal sympathetic nerve activity and elevated levels of plasma norepinephrine. There was decreased expression of nNOS protein (Akita 0.43 ± 0.11 vs. WT 0.75 ± 0.05, P < 0.05) in the PVN of Akita mice. Akita mice had increased expression of angiotensin-converting enzyme (ACE) (Akita 0.58 ± 0.05 vs. WT 0.34 ± 0.04, P < 0.05) and Ang II type 1 receptor (Akita 0.49 ± 0.03 vs. WT 0.29 ± 0.09, P < 0.05), decreased expressions of ACE2 (Akita 0.17 ± 0.05 vs. WT 0.27 ± 0.03, P < 0.05) and angiotensin (1-7) Mas receptor (Akita 0.46 ± 0.02 vs. WT 0.77 ± 0.07, P < 0.05). Futher, there were increased protein levels of protein inhibitor of nNOS (PIN) (Akita 1.75 ± 0.08 vs. WT 0.71 ± 0.09, P < 0.05) with concomitantly decreased catalytically active dimers of nNOS (Akita 0.11 ± 0.04 vs. WT 0.19 ± 0.02, P < 0.05) in the PVN in Akita mice. Our studies suggest that activation of the excitatory arm of RAS, leads to a decrease NO, causing an over-activation of the sympathetic drive in DM.

Comparative Analysis of Host Cell Entry Efficiency and Neutralization Sensitivity of Emerging SARS-CoV-2 Lineages KP.2, KP.2.3, KP.3, and LB.1

New SARS-CoV-2 lineages continue to evolve and may exhibit new characteristics regarding host cell entry efficiency and potential for antibody evasion. Here, employing pseudotyped particles, we compared the host cell entry efficiency, ACE2 receptor usage, and sensitivity to antibody-mediated neutralization of four emerging SARS-CoV-2 lineages, KP.2, KP.2.3, KP.3, and LB.1. The XBB.1.5 and JN.1 lineages served as controls. Our findings reveal that KP.2, KP.2.3, KP.3, and LB.1 lineages enter host cells efficiently and in an ACE2-dependent manner, and that KP.3 is more adept at entering Calu-3 lung cells than JN.1. However, the variants differed in their capacity to employ ACE2 orthologues from animal species for entry, suggesting differences in ACE2 interactions. Moreover, we demonstrate that only two out of seven therapeutic monoclonal antibody (mAbs) in preclinical development retain robust neutralizing activity against the emerging JN.1 sublineages tested, while three mAbs displayed strongly reduced neutralizing activity and two mAbs lacked neutralizing activity against any of the lineages tested. Furthermore, our results show that KP.2, KP.2.3, KP.3, and LB.1 lineages evade neutralization by antibodies induced by infection or vaccination with greater efficiency than JN.1, particularly in individuals without hybrid immunity. This study indicates that KP.2, KP.2.3, KP.3, and LB.1 differ in ACE2 interactions and the efficiency of lung cell entry and suggest that evasion of neutralizing antibodies drove the emergence of these variants.

Tight junction protein LSR is a host defense factor against SARS-CoV-2 infection in the small intestine.

The identification of host factors with antiviral potential is important for developing effective prevention and therapeutic strategies against SARS-CoV-2 infection. Here, by using immortalized cell lines, intestinal organoids, ex vivo intestinal tissues and humanized ACE2 mouse model as proof-of-principle systems, we have identified lipolysis-stimulated lipoprotein receptor (LSR) as a crucial host defense factor against SARS-CoV-2 infection in the small intestine. Loss of endogenous LSR enhances ACE2-dependent infection by SARS-CoV-2 Spike (S) protein-pseudotyped virus and authentic SARS-CoV-2 virus, and exogenous administration of LSR protects against viral infection. Mechanistically, LSR interacts with ACE2 both in cis and in trans, preventing its binding to S protein, and thus inhibiting viral entry and S protein-mediated cell-cell fusion. Finally, a small LSR-derived peptide blocks S protein binding to the ACE2 receptor in vitro. These results identify both a previously unknown function for LSR in antiviral host defense against SARS-CoV-2, with potential implications for peptide-based pan-variant therapeutic interventions.

Design and Test of Molecules that Interfere with the Recognition Mechanisms between the SARS-CoV-2 Spike Protein and Its Host Cell Receptors.

The disruptive impact of the COVID-19 pandemic has led the scientific community to undertake an unprecedented effort to characterize viral infection mechanisms. Among these, interactions between the viral glycosylated Spike and the human receptors ACE2 and TMPRSS2 are key to allowing virus invasion. Here, we report and test a fully rational methodology to design molecules that are capable of perturbing the interactions between these critical players in SARS-CoV-2 pathogenicity. To this end, we computationally identify substructures on the fully glycosylated Spike protein that are not intramolecularly optimized and are thus prone to being stabilized by forming complexes with ACE2 and TMPRSS2. With the aim of competing with the Spike-mediated cell entry mechanisms, we have engineered the predicted putative interaction regions in the form of peptide mimics that could compete with Spike for interaction with ACE2 and/or TMPRSS2. Experimental models of viral entry demonstrate that the designed molecules are able to interfere with viral entry into ACE2/TMPRSS2 expressing cells, while they have no effects on the entry of control viral particles that do not harbor the Spike protein or on the entry of Spike-presenting viral particles into cells that do not display its receptors on their surface.

Antibodies as Promising Molecules to Block Spike Glycoprotein from SARS-CoV2

Abstract: COVID-19 is caused by a new SARS-CoV-2 virus from the Coronaviridae family, responsible for developing severe acute respiratory syndrome (SARS-CoV). Its emergence in 2019 presented several challenges to global health. The virus can infect host cells using the ACE2 receptor, and after infection, several clinical manifestations appear, ranging from mild symptoms to death. One approach that has shown promising results is convalescent plasma since convalescent plasma (CP) consists of a concentrate of immunoglobulins in the blood of patients recently infected with the coronavirus for those currently infected. Therefore, this therapy uses antibodies in the plasma to neutralize the virus. This literature review aims to evaluate the efficacy of CP therapy in symptomatic COVID-19 patients by analyzing clinical trials and studies published between 2020 and 2023. Therefore, the search identified studies in which the majority reported the efficacy of using convalescent plasma to treat and alleviate the clinical condition of patients diagnosed with COVID-19. Important factors influence the efficacy of CP therapy, such as the timing of administration and the severity of the disease. Early administration in mild and moderate cases has shown promise. Furthermore, molecular docking analysis suggests that antibodies can cause conformational changes in the SARS-CoV-2 spike protein, raising the hypothesis that using CP may interfere with viral entry into host cells.

COVID-19 – a Five-Year Update

Background: This review aims to categorically describe novel advancements to our understanding and management of COVID-19 and associated short- and long-term sequelae such as Long COVID. Methods: Indexing services (Scopus and PubMed) were used to identify pertinent studies, prioritizing original research, meta reviews and updated institutional guidelines from 2022 onwards. Papers not published in English (or where full-text translation was not available), those skewed in terms of gender distribution of participants, conducted on non-human populations and proposal and opinion papers were excluded. For the purposes of this paper, Long COVID was taken to mean the persistence of symptoms longer than 8 weeks after an acute COVID-19 infection. After deduplication, application of the exclusion criterion and checking for relevance, 52 sources were identified for this review. The keywords used for this literature search were COVID-19, Long COVID, Chronic COVID, SARS-CoV-2. Results: New COVID-19 variants challenge vaccine efficacy, highlighting socioeconomic disparities in vaccination rates. Long COVID exhibits complex symptoms, including cognitive decline and physical health impacts. The virus’s affinity for ACE-2 receptors suggests broader health implications, including reproductive and metabolic disorders. COVID-19 can cause a drop in IQ proportional to severity of disease experienced. Conclusion: COVID-19’s multifaceted health impacts necessitate ongoing research and targeted interventions. Addressing socioeconomic disparities, updating vaccine formulations, and understanding long-term effects are crucial. Equitable healthcare policies are essential to mitigate COVID-19’s global health threat and inform future strategies.

Animal Models in COVID-19 Research: Insights and Outcomes

Animal models have been critical in understanding the pathogenesis, transmission, and therapeutic interventions for COVID-19, caused by SARS-CoV-2. The primary challenges include species-specific differences in viral receptor expression, particularly the ACE2 receptor, and immune system responses, which can affect how closely these models mimic human COVID-19 pathology. Additionally, ethical concerns around the use of animals, especially non-human primates, and logistical issues such as high costs, housing requirements, and limited availability of certain models, further complicate research efforts. Transgenic mice expressing human ACE2 (hACE2) are widely used because of their ease of handling and cost-effectiveness. Other animal models include non-human primates, hamsters, cats, and ferrets, which were used to study viral transmission and host-pathogen interactions. The rapid dynamics of the SARSCoV-2 evolution is one of the challenges and the complementary use of multiple models provides a more comprehensive understanding of the disease. Nonetheless, these models have been essential for rapid advancements in COVID19 vaccine and therapeutic development, offering insights that continue to guide public health strategies. The review discusses the various animal models used in SARS-CoV-2 research, the outcomes, and the challenges and questions to be addressed Keywords: Animal models, SARS-CoV-2, COVID-19

Association of Angiotensin Converting Enzyme Phenotypes and Polymorphisms with Clinical Outcomes in SARS-CoV2 Patients with Hypertension in an Urban Emergency Department.

The role of Angiotensin-converting enzyme (ACE and ACE2) phenotypes and polymorphisms in modulating severe acute respiratory syndrome coronavirus (SARS-- CoV2) infection in hypertensive patients remains unclear. Our objective was to determine the distribution of ACE and ACE2 receptor phenotypes by patient demographics and correlate ACE and ACE2 levels of activity with SARS-CoV-2 outcomes. Hypertensive patients treated for SARS-CoV-2 at an urban emergency department (ED) were prospectively enrolled in a cohort study between August 2020 and April 2021. Blood samples were collected during ED visits or hospitalization. Outcome measures including hospitalization, intensive care unit (ICU) admission, and 30-day mortality were obtained from electronic health records. Multivariable logistic regression was used. Of the 150 patients enrolled, 60% were Black, 32% Hispanic/Latinx, 4% Non-Hispanic Whites, and 4% others. The mean age was 59 (+/-14) years. The rate of hospitalization was high (86%) and Hispanic/Latinx had a higher likelihood of ICU admission. Patients harboring the rs2285666 genotype TT, AA, and GC alleles were more likely to be admitted to ICU, and those with TT and AA had higher mortality. The ACE level was a significant predictor of hospitalization with a protective effect in both unadjusted and adjusted results. Hispanics/Latinx had a four times higher likelihood of ICU admission compared to all others, and age was significantly associated with 30-day mortality. Our results show that even after adjusting for age, race, and sex, ACE levels remained a predictor of hospitalization. ACE/ACE2 phenotypes and genotypes potentially play an important role in disease progression in SARS-CoV-2 patients.

Assessment of Binding Affinity in the Complexes of CoV-S-Protein’s RBD and the ACE2 Using Convolutional Neural Networks

The experimentally obtained structures of 48 complexes of the ACE2 receptor with the S protein’s RBD of the coronaviruses SARS-CoV and SARS-CoV-2 (including mutant forms of the latter) were assessed and the dissociation constant was calculated for them. Prediction of binding affinity was carried out using ProBAN, a neural network algorithm, previously developed by the authors, and a number of other algorithms for estimating the Gibbs free energy such as Prodigy, FoldX, DFIRE and RosettaDock. A comparison of the evaluation results shows that ProBAN has the best prediction quality (Pearson correlation − 0.56, MAE − 0.7 kcal/mol) of all the analyzed algorithms. The results obtained suggest better quality of affinity prediction for other protein-protein complexes. Information about the complexes under study and prediction results are available in the repository at the link: https://github.com/EABogdanova/ProBAN_RBD-ACE2.

The accomplices: Heparan sulfates and N-glycans foster SARS-CoV-2 spike:ACE2 receptor binding and virus priming

Although it is well established that the SARS-CoV-2 spike glycoprotein binds to the host cell ACE2 receptor to initiate infection, far less is known about the tissue tropism and host cell susceptibility to the virus. Differential expression across different cell types of heparan sulfate (HS) proteoglycans, with variably sulfated glycosaminoglycans (GAGs), and their synergistic interactions with host and viral N-glycans may contribute to tissue tropism and host cell susceptibility. Nevertheless, their contribution remains unclear since HS and N-glycans evade experimental characterization. We, therefore, carried out microsecond-long all-atom molecular dynamics simulations, followed by random acceleration molecular dynamics simulations, of the fully glycosylated spike:ACE2 complex with and without highly sulfated GAG chains bound. By considering the model GAGs as surrogates for the highly sulfated HS expressed in lung cells, we identified key cell entry mechanisms of spike SARS-CoV-2. We find that HS promotes structural and energetic stabilization of the active conformation of the spike receptor-binding domain (RBD) and reorientation of ACE2 toward the N-terminal domain in the same spike subunit as the RBD. Spike and ACE2 N-glycans exert synergistic effects, promoting better packing, strengthening the protein:protein interaction, and prolonging the residence time of the complex. ACE2 and HS binding trigger rearrangement of the S2' functional protease cleavage site through allosteric interdomain communication. These results thus show that HS has a multifaceted role in facilitating SARS-CoV-2 infection, and they provide a mechanistic basis for the development of GAG derivatives with anti-SARS-CoV-2 potential.

Identification and genetic characterization of five novel bat coronaviruses from Yunnan, China

BackgroundCoronaviruses (CoVs) represent a serious threat to human health and have become a major transmissible, endemic, and causative pathogen in humans; they represent a major health concern, given their ability to cause infectious diseases. Bats are natural hosts for diverse viruses. Many transmission events of CoVs and identification of multiple novel CoVs in bats has increased attention towards their capacity to serve as hosts for zoonotic viruses.ResultsIn this study, 61 bats from Yunnan Province were analyzed, identifying seven CoVs, including three α- and two β-CoVs with full-genome sequences. Among the five identified alpha-CoVs, four belong to the Decacovirus subgenus and one to the Minunacovirus subgenus. Two beta-CoVs were also identified, both belonging to the Sarbecovirus subgenus.The genetic structures revealed similarities to known strains such as HKU10 and SARS-CoV-2, along with novel findings such as the Minunacovirus subgenus CoV YJ3c/f and unique ORF patterns. Our results demonstrated that strain JCC9 has a unique recombination pattern and shows a higher binding affinity to civet and pangolin ACE2 receptors, then the HpJC8xc strain transmits and recombines between hosts (bats), indicating a potential risk of crossing the interspecies barrier and infecting other animals.ConclusionsThe CoVs detected in the bats studied in this research exhibit high diversity. Genomic analysis revealed that CoVs in bats undergo frequent recombination events. Furthermore, recombination patterns and evolutionary analyses suggest that alpha-CoVs are more prone to cross-species transmission across different bat families/genera, whereas beta-CoVs demonstrate host specificity and tend to co-evolve with their bat hosts.Our finding suggest that bats, as hosts of CoVs, be constantly monitored to prevent outbreaks of new infections caused by viruses passing across interspecies barriers, and consequently, viral diseases in humans or livestock.

Polypurine reverse hoogsteen hairpins as a therapeutic tool for SARS-CoV-2 infection

Although COVID-19 pandemic was declared no longer a global emergency by the World Health Organization in May 2023, SARS-CoV-2 is still infecting people across the world. Many therapeutic oligonucleotides such as ASOs, siRNAs or CRISPR-based systems emerged as promising antiviral strategies for the treatment of SARS-CoV-2. In this work we explored the inhibitory potential on SARS-CoV-2 replication of Polypurine Reverse Hoogsteen Hairpins (PPRHs), CC1-PPRH and CC3-PPRH, targeting specific polypyrimidine sequences within the replicase and Spike regions, respectively, and previously validated for COVID-19 diagnosis. Both PPRHs bound to their target sequences in the viral genome with high affinity in the order of nM. In vitro, both PPRHs reduced viral replication by more than 92% when transfected into VERO-E6 cells 24 hours prior infection with SARS-CoV-2. In vivo intranasal administration of CC1-PPRH in K18-hACE2 mice expressing the human ACE receptor protected all the animals from SARS-CoV-2 infection. The properties of PPRHs position them as promising candidates for the development of novel therapeutics against SARS-CoV-2 and other viral infections.

In silico study of lactoferrin as an anticancer, anti-viral, and anti-bacterial bioactive compound and disease diagnostic marker.

Studying the interaction of proteins and genes by current computational methods is effective in new drug design. Considering the special role of lactoferrin (Lf) identifying its action mechanism is a new gate to the targeted treatment of some diseases. This study aimed to investigate the molecular interaction of Lf with virus spike, the bacterial cell binding receptor, and the proteins involved in apoptosis by in silico research. The docking results showed that the amino acids involved in the interaction between the spike virus of COVID-19 with the ACE2 receptor were similar to the amino acids in the interaction between the virus spike and Lf, and the binding between Lf and the viral spike was more inclined. The N-terminus of Lf interacted with the N-terminus region of the CD14, which contains the binding sites of bacterial lipopolysaccharide to the cell. Lf can compete for binding with bacterial lipopolysaccharides. The results related to the docking of TP53, BAX, and BAK1 gene promoters and Lf showed that Lf with one or more amino acids that are responsible for binding to DNA interacted with TP53 and BAX genes with higher binding affinity. In all protein and protein-gene interactions, the N-lobe region of Lf, which is its functional region, is involved in these interactions, and the anticancer, antibacterial, and antiviral, roles of Lf are related to this region. Lf is important as a medicinal supplement for treating COVID-19 and cancer.

COVID-19 and Reproductive Function: A Detailed Review of Fertility Outcomes, Sperm Alterations, and Vertical Transmission Concerns

Background:The global COVID-19 pandemic, caused by SARS-CoV-2, raises concerns about its effects on reproductive health. Emerging evidence suggests potential impacts on male and female fertility, including hormonal changes, immune responses, and organ damage, though the virus’s direct influence on reproductive tissues and vertical transmission remains unclear. Objective:This review summarizes current evidence on COVID-19’s effects on male and female reproductive health, focusing on sperm count, fertility, and vertical transmission. Methods:A comprehensive literature review was conducted using databases such as PubMed, Scopus, and Web of Science. Peer-reviewed studies were included based on their relevance to reproductive outcomes, sperm count, hormonal changes, and vertical transmission of SARS-CoV-2. Results:Most studies found no direct evidence of SARS-CoV-2 in male or female reproductive tissues. However, a temporary decline in sperm count and quality has been reported in men recovering from COVID-19. Hormonal fluctuations, particularly increased luteinizing hormone (LH) levels, were observed in some male patients. In females, the presence of ACE2 receptors in reproductive organs suggests a potential risk, but no conclusive evidence of impaired fertility has been found. Vertical transmission remains uncertain, with isolated cases reporting elevated IgM antibodies in newborns. Conclusion:Although direct evidence of SARS-CoV-2 impacting fertility is limited, temporary reproductive disruptions in males, including reduced sperm count, have been noted. The risk of vertical transmission remains unclear. Further research is essential to determine COVID-19’s long-term reproductive effects.

Effect of Phyto Constitutes of &lt;i&gt;Ayurveda&lt;/i&gt; and &lt;i&gt;Siddha&lt;/i&gt; Herbs on SARS-CoV-2/CoVID-19 Management by Modulating the Human Gut Microbiome

The therapeutic plants used in Ayurveda and Siddha medicine primarily function as immunomodulators to combat viral infection. The majority of the Indian states adopted an integrative approach to the treatment strategy for COVID-19 infection during the COVID-19 outbreak. A large percentage of Indians consume Ayurvedic and Siddha herbs as preventative medication or immune boosters during the COVID outbreak. ACE-2 receptor, Mpro, Nsp15, endoribonuclease, ACE-2-RBD interface, RBD complex, helicase inhibitors, and ACE-2-RBD interface are the main targets of the phytochemicals of medicinal plants, which also have the potential to limit their action and lower infection rates. The phytonutrients also preserve the permeability of the gut epithelial membrane and improve gut barrier proteins including occludin, Zo-1, and claudin. The phytonutrients also help probiotic bacteria flourish, such as Faecalibacterium, Rikenellaceae, Lactobacillus and Lachnospiraceae, which may lower proinflammatory cytokines and improve immunological function. A small number of opportunistic bacteria, such as Pseudomonas aeruginosa and Klebsiella pneumonia, co-infect with the SARS-CoV-2 virus and increase the frequency of hospital stays and severity of the illness. The co-infections or secondary infections may be reduced by the antibacterial and anti-inflammatory activities of phytochemicals.