Antiviral Research Articles

Synthesis of 1-Substituted Bicyclo[2.1.1]hexan-2-ones via a Sequential SmI2-Mediated Pinacol Coupling and Acid-Catalyzed Pinacol Rearrangement Reaction.

A two-step procedure, combining a SmI2-mediated transannular pinacol coupling reaction with an acid-catalyzed pinacol rearrangement process, was employed to prepare a diverse range of 1-substituted bicyclo[2.1.1]hexan-5-ones from cyclobutanedione derivatives. To underscore the significance of these bicyclic ketones in drug synthesis, an sp3-rich analog of nitazoxanide, a well-known antiparasitic and antiviral agent, was synthesized.

DFT, Molecular Docking, ADME, and Cardiotoxicity Studies of Persuasive Thiazoles as Potential Inhibitors of the Main Protease of SARS-CoV-2.

This study explores the capability of thiazoles as potent inhibitors of SARS-CoV-2 Mpro. Seventeen thiazoles (1-17) were screened for their linking affinity with the active site of SARS-CoV-2 Mpro and compared with the FDA-recommended antiviral drugs, Remdesivir and Baricitinib. Density Functional Theory (DFT) calculations provided electronic and energetic properties of these ligands, shedding light on their stability and reactivity. Molecular docking analysis revealed that thiazole derivatives exhibited favorable linking affinities with various functional sites of SARS-CoV-2 proteins, including spike receptor-linking zone, nucleocapsid protein N-terminal RNA linking zone, and Mpro. Notably, compounds 3, 10, and 12 displayed the best interaction with 6LZG as compared to FDA-approved antiviral drugs Remdesivir and Baricitinib, while compounds 1, 10, and 8 exhibited strong linking with 6 M3 M and also better than Remdesivir and Baricitinib. Additionally, compounds 3, 1, and 6 showed promising interactions with 6LU7 but only compound 3 performed better than Baricitinib. An ADME (Absorption, Distribution, Metabolism, and Excretion) study provided insights into the pharmacokinetics and drug-likeness of these compounds, with all ligands demonstrating good physicochemical characteristics, lipophilicity, water solubility, pharmacokinetics, drug-likeness, and medicinal chemistry attributes. The results suggest that these selected thiazole derivatives hold promise as potential candidates for further drug development.

Pre-training strategy for antiviral drug screening with low-data graph neural network: A case study in HIV-1 K103N reverse transcriptase.

Graph neural networks (GNN) offer an alternative approach to boost the screening effectiveness in drug discovery. However, their efficacy is often hindered by limited datasets. To address this limitation, we introduced a robust GNN training framework, applied to various chemical databases to identify potent non-nucleoside reverse transcriptase inhibitors (NNRTIs) against the challenging K103N-mutated HIV-1 RT. Leveraging self-supervised learning (SSL) pre-training to tackle data scarcity, we screened 1,824,367 compounds, using multi-step approach that incorporated machine learning (ML)-based screening, analysis of absorption, distribution, metabolism, and excretion (ADME) prediction, drug-likeness properties, and molecular docking. Ultimately, 45 compounds were left as potential candidates with 17 of the compounds were previously identified as NNRTIs, exemplifying the model's efficacy. The remaining 28 compounds are anticipated to be repurposed for new uses. Molecular dynamics (MD) simulations on repurposed candidates unveiled two promising preclinical drugs: one designed against Plasmodium falciparum and the other serving as an antibacterial agent. Both have superior binding affinity compared to anti-HIV drugs. This conceptual framework could be adapted for other disease-specific therapeutics, facilitating the identification of potent compounds effective against both WT and mutants while revealing novel scaffolds for drug design and discovery.

Regulation of expression of unintegrated and integrated HIV-1 DNA: keeping the wolves at bay

The unintegrated HIV-1 DNAs formed by reverse transcription in the early hours after infection are subject to profound transcriptional silencing. The repression of expression of foreign DNA, as an aspect of the innate immune system, serves to restrict the activity of many invading pathogens. Newly formed retroviral DNAs are rapidly loaded with histones upon entry into the nucleus, and the repression of their expression is mediated by an array of host proteins that introduce histone modifications characteristic of heterochromatin, including histone methylation and histone deacetylation. Knockout or knockdown of expression or inhibition of these host factors can relieve the silencing, allowing for viral gene expression even in settings where HIV-1 DNA integration is blocked. When viral DNA integration is allowed, forming the integrated provirus, the silencing in most cases is dramatically relieved, leading to high levels of expression and formation of progeny virus. In some settings and cell types, silencing of the integrated DNA is maintained, or re-established, such that the infected cells retain a silent copy of the viral DNA without production of progeny virus. The basis for the typical switch from silent DNA to actively expressed DNA upon integration is not yet fully clear. This review will summarize the current understanding of the regulation of expression of unintegrated HIV-1 DNAs and the nature of the chromatin that is formed on the viral DNA, and will especially focus on the host machinery that establishes repressive heterochromatin-like structures on the unintegrated DNA. The activation of expression that normally occurs upon integration, and the special circumstances when viral DNA expression is not activated, will also be discussed. These cases can result in the formation of populations of infected cells carrying silent proviruses, which persist for decades in infected individuals in spite of antiviral therapy. This pool of latently infected cells can be stochastically reactivated to give rise to spreading virus whenever antiviral drugs are withdrawn, and constitute the barrier to a true “cure” of AIDS. The hope is that a deeper understanding of the regulation of expression of viral DNAs will lead to new means to prevent or control viremia and disease.

Congenital Cytomegalovirus Infection: Update on Screening, Diagnosis and Treatment: Scientific Impact Paper No. 56.

Cytomegalovirus (CMV) is the most common cause of viral infection in newborn babies, and affects 1 in 200 of all live born infants in high-income countries; and 1 in 71 in low- and middle-income countries. It is a major cause of hearing loss and brain damage. Women may get CMV infection for the first time during pregnancy (primary infection) or may experience 'non-primary' infection, either by reactivation of previous CMV infection or by a new infection with a different strain of the virus. The most common source of infection to pregnant women is the saliva and urine of young children. Therefore, all pregnant women, especially those in regular contact with young children, should be informed about hygiene-based measures to reduce the risks, e.g. handwashing. The UK National Screening Committee recommends against universal antenatal or newborn screening for CMV. Testing for CMV is usually offered only to women who develop symptoms of influenza, glandular fever or hepatitis (liver inflammation) during pregnancy, or for those whom a routine ultrasound scan detects fetal anomalies that suggests possible CMV infection. The risk of harm to the fetus is greatest following primary CMV infection of the woman in early pregnancy, and appears to be very low following infection after 12 weeks of pregnancy. Babies with CMV infection at birth may have jaundice, a rash, enlarged liver or spleen, a small brain, or be small for their gestational age. Around 1 in 8 babies born with CMV infection will have clinically detectable signs at birth. The rest will not have any features detectable by clinical examination alone. Therefore, all infants with CMV infection at birth should be followed up at a minimum of up to 2 years of age or later, depending upon the disease status, to check hearing and brain development. Following primary CMV infection in the first 12 weeks of pregnancy, if the woman starts taking the antiviral medicine valaciclovir (valacyclovir) it reduces the risk of the baby becoming infected. Where CMV infection of the fetus in the womb has been confirmed (by amniocentesis, for example), regular ultrasound scans should be offered every 2-3 weeks until birth. Detailed assessment of the fetal brain is an essential part of these scans. Where maternal CMV infection occurs, but fetal infection is not confirmed, repeated ultrasound scans of the fetus should be offered every 2-3 weeks until birth. In infected fetuses, as well as ultrasound scans, an MRI scan of the brain should be offered at 28-32 weeks of gestation (and sometimes repeated 3-4 weeks later) to assess for any signs of harm to the fetal brain. All babies born to women with confirmed or suspected CMV infection should be tested for CMV with a urine or saliva sample within the first 21 days of life. In newborns with symptomatic CMV infection at birth, treatment with antiviral medicine (valganciclovir or ganciclovir) can reduce hearing loss in 5 out of 6 babies, and improve long-term brain development outcomes in some. There is no licensed vaccine for CMV.

HCV genotype distribution in Istanbul: Adetailed 7 year epidemiological overview andimpact of Covid-19 pandemic.

Hepatitis C virus (HCV) is a leading cause of chronic liver disease, cirrhosis, and hepatocellular carcinomaworldwide. HCV has 8 genotypes (GT) and 86 subtypes and distribution of GTs varies based on geographical regions, transmission routes and even in cultural groups. The determination of viral genotype is crucial in choosing antiviral treatment, determining the duration of therapy, and monitoring treatment respose. Since 2014, with the usage of direct-acting antiviral agents (DAAs) in the treatment of HCV infections, a cure rate over 95% could be possible. Epidemiological data are important to combat a chronic HCV infections. Due to its geographical location, Turkey is like a bridge connecting Asia and Europe. Istanbul is the biggest and most crowded city of Turkey and has received immigration from many different countries, especially from Syria, in recent years and immigration still goes on. In addition, the COVID-19 pandemic has had devastating effects in our country. In this study, we determined the HCV genotypes in Health Sciences University Ümraniye Training and Research Hospital, in Istanbul between 2016 and 2022. Of the 322 patients analyzed during this 7-year period, HCV GT1b was the most prevalent GT in 65.2%, followed by GT3 in 15.5%, GT1a in 10.6%. Our data serve as a great mirror for HCV epidemiology in Turkey and contribute to global data.

Cytokine production in an ex vivo model of SARS-CoV-2 lung infection

IntroductionThe mechanisms of the SARS-CoV-2-triggered complex alterations in immune cell activation and production of cytokines in lung tissue remain poorly understood, in part because of the limited use of adequate tissue models that simulate the structure and cell composition of the lung in vivo. We developed a novel ex vivo model of SARS-CoV-2 infection of lung explants, that maintains the intact tissue composition and the viral load for up to 7–10 days. Using this model, we studied cytokine production during SARS-CoV-2 infection.Materials and methodsLung tissue was monitored for viability and cell composition using flow cytometry and histological analysis. SARS-CoV-2 infection was verified immunohistochemically, viral loads in tissue and culture medium were monitored by qPCR. A panel of 41 cytokines was measured in culture medium using xMAP technology.ResultsThe explant lung tissue was viable and maintained viral infection that influenced the cytokine production. Elevated concentrations of G-CSF, GM-CSF, GRO-a, IFN-g, IL-6, IL-8, IP-10, MCP-3, MIP-1a, PDGF-AA, and VEGF, and decreased IL-1RA concentration were observed in infected tissue compared to non-infected tissue.DiscussionOur results generally reflect the data obtained in COVID-19 patients. GRO-a, IFN-g, IL-6, IL-8, MCP-1, MCP-3, and RANTES correlated with the viral load, forming a distinct pro-inflammatory cluster. Thus, our lung ex vivo model faithfully reproduces some aspects of cytokine alterations in COVID-19 patients at an early disease stage, making the investigation of SARS-CoV-2 infection mechanisms more accessible and providing a potential platform for antiviral drug testing.

A Novel Peptide from VP1 of EV-D68 Exhibits Broad-Spectrum Antiviral Activity Against Human Enteroviruses

Enteroviruses have been a historical concern since the identification of polioviruses in humans. Wild polioviruses have almost been eliminated, while multiple species of non-polio enteroviruses and their variants co-circulate annually. To date, at least 116 types have been found in humans and are grouped into the species Enterovirus A–D and Rhinovirus A–C. However, there are few available antiviral drugs, especially with a universal pharmaceutical effect. Here, we demonstrate that peptide P25 from EV-D68 has broad antiviral activity against Ev A–D enteroviruses in vitro. P25, derived from the HI loop and β-I sheet of VP1, operates through a conserved hydrophilic motif -R---K-K--K- and the hydrophobic F near the N-terminus. It could prevent viral infection of EV-A71 by competing for the heparan sulfate (HS) receptor, and binding and stabilizing virions by suppressing the release of the viral genome. P25 also inhibited the generation of infectious viral particles by reducing viral protein synthesis. The molecular docking revealed that P25 might bind to the pocket opening area, a potential target for broad-spectrum antivirals. Our findings implicate the multiple antiviral effects of peptide P25, including blocking viral binding to the HS receptor, impeding viral genome release, and reducing progeny particles, which could be a novel universal anti-enterovirus drug candidate.

The risk of postherpetic neuralgia in COVID-19 vaccination-associated herpes zoster: A retrospective cohort study using TriNetX

BackgroundThe administration of the COVID-19 vaccine has been linked to the development of herpes zoster (HZ). However, studies examining the clinical outcomes in COVID-19 vaccination-associated and non-COVID-19 vaccination-associated HZ are lacking. ObjectiveTo investigate the risk of postherpetic neuralgia in COVID-19 vaccination associated HZ. MethodsA total of 7200 patients with COVID-19 vaccination-associated HZ and 7200 matched controls were enrolled from the US Collaborative Network in the TriNetX database. The main outcome of this study was the development of PHN.Patients were followed-up from 3 months after HZ until PHN diagnoses, withdrawal from the database, or October 8, 2024. ResultsWe observed that patients with COVID-19 vaccination-associated HZ had a significantly higher risk of developing PHN as compared to the control group, with hazard ratio of 1.69 (> 3 months), 1.80 (> 6 months), 1.86 (> 1 year), and 1.93 (>2 years), respectively. Additionally, the association remained significant in the stratified analysis, which included sex, age, malignancy status, and initial use of antiviral agents. ConclusionThis study showed that COVID-19 vaccination-associated HZ demonstrated a significantly higher risk of developing PHN.

Antiviral effects of Sarcodia suae water extracts against vesicular stomatitis virus infection

ABSTRACT Marine algae, a rich source of bioactive substances, have long been utilized in biomedical and veterinary sciences. This study breaks new ground by assessing the antiviral therapeutic potential of water extracts from four algal species – Colaconema formosanum, Caulerpa microphysa, Gelidium amansii and Sarcodia suae – against vesicular stomatitis virus (VSV) infection. The standout among these was Sarcodia suae water extract (SSWE), which not only significantly repressed VSV replication and enhanced cell survival without cytotoxic effects, but also demonstrated its antiviral activity through interference with viral attachment, entry, RNA replication, and egress, and reduced VSV-induced autophagy in Mv1Lu cells during the late stages of infection. The EC50 of SSWE was 0.422 ± 0.14 mg ml‒1. The cytotoxicity assay confirmed the high biocompatibility of SSWE. This study identifies SSWE as a promising natural antiviral agent and elucidates its mechanisms of action, highlighting the need for further research to optimize its use in controlling VSV-related diseases.

Chronic hepatitis B, Extrahepatic Malignancies and the Use of Antiviral Drugs.

Chronic hepatitis B, Extrahepatic Malignancies and the Use of Antiviral Drugs.

Vitamin D: A key player in COVID-19 immunity and lessons from the pandemic to combat immune-evasive variants.

As of the 7th of July 2024, 775,754,322 confirmed cases of COVID-19, including 7,053,902 deaths worldwide, had been reported to the WHO (World Health Organization). Nevertheless, untill the 15th of July 2024, a total of 13,578,710,228 vaccine doses had been administered, with almost no country spared from COVID-19 attacks. The pathophysiology of this virus is complicated, and several symptoms require a deep understanding of the actual mechanisms. It is unclear why some patients develop severe symptoms while others do not, although literature suggests a role for vitamin D. Vitamin D plays a crucial role in the infection or in ameliorating the severity of symptoms. The mechanism of action of vitamin D and vitamin D deficiency (VDD) is well understood. VDD is associated with increased hospitalization of severely ill patients and increased levels of COVID-19-caused mortality. Recent studies suggest that vitamin D levels and genetic variations in the vitamin D receptor (VDR) gene significantly impact the severity and outcomes of COVID-19, especially in the infections caused by Delta and Omicron variants. Furthermore, VDD causes immune system dysregulation upon infection with SARS-CoV-2, indicating that vitamin D sufficiency is crucial in fighting against COVID-19 infection. The therapeutic effect of vitamin D raises interest in its potential role as a prophylactic and treatment adjunct. We evaluate the immunomodulatory effects of vitamin D and its ability to enhance the efficacy of new antiviral drugs like molnupiravir and paxlovid against SARS-CoV-2. This review discusses the role of vitamin D sufficiency and VDD in COVID-19 initiation and progression, emphasizing the molecular mechanisms by which vitamin D exerts its actions as a proactive step for the next pandemic. However, there is still no clear evidence of vitamin D's impact on prevention and treatment, leading to contradictory findings. Therefore, large-scale randomized trials are required to reach a definitive conclusion. A bibliometric analysis of publications related to vitamin D, immunity, and COVID-19 revealed a significant increase in research activity in this area, particularly in 2020-2024, underscoring the growing recognition of vitamin D's potential role in the context of the pandemic.

Building Metabolically Stable and Potent Anti-HIV Thioether-Lipid Analogues of Tenofovir Exalidex: A thorough Pharmacological Analysis.

Inherently limited by poor bioavailability, antiviral agent tenofovir (TFV) is administered to people living with HIV in prodrug form. However, current prodrugs are prematurely metabolized, compromising access to HIV-infected cells and inducing toxicity. Inspired by lipid conjugate TFV exalidex (TXL), we recently disclosed TXL analogs with potent activity and robust hepatic stability in vitro, as well as attractive oral PK profiles in vivo. In parallel, we discovered the equipotent and equally stable hexadecylthiopropyl (HTP) derivative of TXL (2a). Reported herein are the synthetic and bioanalytic efforts that led to potent, safe, and hepatically stable HTP derivatives. While HTP analog 16h showed the most attractive PK profile in mice (55% F) discrepancies in translating in vitro cell-based results to in vivo PK data, for certain prodrugs, indicated that further in vitro/in vivo optimization is required for continued advancement of this program.

Clinical efficacy and safety of new compound single tablet antiviral drugs in the treatment of HIV/AIDS

AimsGenvoya, Biktarvy and Dovato are novel single-tablet antiretroviral therapy(ART). The aim of this study is to explore the therapeutic effects of these novel drugs on HIV/AIDS. Main methodsThis retrospective cohort study, conducted at a single center, included a total of 200 HIV-treated patients who transitioned to these new antiretroviral drugs from July 2021 to August 2023. Data were extracted from electronic medical records at Ditan Hospital. The Genvoya group comprised 22 patients, and all subsequent switches in this group were to Biktarvy. The primary HAART group consisted of 178 patients initially treated with a first-line triple Highly Active Antiretroviral Therapy (HAART) regimen during the same period. This group was further subdivided into HAART+Dovato, HAART+Biktarvy, and HAART+Genvoya groups based on the switching regimen. The primary outcomes focused on changes in viral load and immune efficacy, while secondary safety indicators included blood/liver function, lipid parameters, renal function, blood glucose, blood uric acid, etc. Key findingsThe viral suppression rate was 100 % after the drug change treatment, and CD4+ T cell counts increased significantly across all four groups. Over the 6-month treatment period, there were increases in creatinine (Cr), low-density lipoprotein (LDL), high-density lipoprotein (HDL), erythrocyte count, and glomerular filtration rate (eGFR). Conversely, Alanine transaminase (ALT), Aspartate aminotransferase (AST), C-reactive protein (CRP), albumin (ALB), and blood glucose (Glu) levels decreased. SignificanceGenvoya, Biktarvy and Dovato are recommended for the treatment of HIV/AIDS and have a good safety profile.

Diphyllin elicits a doubled-pronged attack on the entry of SARS-CoV-2 by inhibiting cathepsin L and furin

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the coronavirus disease 2019 (COVID-19) pandemic, posing serious threats to global health. Effective broad-spectrum antiviral drugs for the treatment of COVID-19 are not sufficiently available. In the present study, we investigated the antiviral activity of the natural lignan diphyllin (PubChem CID 100492) against different SARS-CoV-2 variants and explored the underlying molecular mechanisms. We found that diphyllin dose-dependently inhibits the SARS-CoV-2 spike (S)-mediated entry into different types of cells. The potent inhibition was evident against spike proteins derived from the original SARS-CoV-2 and from variants of concern such as Alpha, Beta, Delta or Omicron. Accordingly, diphyllin also significantly inhibited the in vitro infection of a clinical SARS-CoV-2 virus isolate. Mechanistically, diphyllin simultaneously inhibited the endosomal entry of SARS-CoV-2 by neutralizing the endosomal acidification and reducing the activity of the cysteine protease cathepsin L (CTSL) as well as S-meditated cell surface entry by impairing furin activity. Collectively, our findings establish diphyllin as novel inhibitor of CTSL and furin proteases, resulting in a double-pronged attack on SARS-CoV-2 entry along endosomal as well as cell surface routes. Therefore, diphyllin has the potential to be advanced as an inhibitor of SARS-CoV-2 entry.

SARS-CoV-2 N protein coordinates viral particle assembly through multiple domains.

Increasing evidence suggests that mutations in the nucleocapsid (N) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may enhance viral replication by modulating the assembly process. However, the mechanisms governing the selective packaging of viral genomic RNA by the N protein, along with the assembly and budding processes, remain poorly understood. Utilizing a virus-like particles (VLPs) system, we have identified that the C-terminal domain (CTD) of the N protein is essential for its interaction with the membrane (M) protein during budding, crucial for binding and packaging genomic RNA. Notably, the isolated CTD lacks M protein interaction capacity and budding ability. Yet, upon fusion with the N-terminal domain (NTD) or the linker region (LKR), the resulting NTD/CTD and LKR/CTD acquire RNA-dependent interactions with the M protein and acquire budding capabilities. Furthermore, the presence of the C-tail is vital for efficient genomic RNA encapsidation by the N protein, possibly regulated by interactions with the M protein. Remarkably, the NTD of the N protein appears dispensable for virus particle assembly, offering the virus adaptive advantages. The emergence of N* (NΔN209) in the SARS-CoV-2 B.1.1 lineage corroborates our findings and hints at the potential evolution of a more streamlined N protein by the SARS-CoV-2 virus to facilitate the assembly process. Comparable observations have been noted with the N proteins of SARS-CoV and HCoV-OC43 viruses. In essence, these findings propose that β-coronaviruses may augment their replication by fine-tuning the assembly process.IMPORTANCEAs a highly transmissible zoonotic virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to evolve. Adaptive mutations in the nucleocapsid (N) protein highlight the critical role of N protein-based assembly in the virus's replication and evolutionary dynamics. However, the precise molecular mechanisms of N protein-mediated viral assembly remain inadequately understood. Our study elucidates the intricate interactions between the N protein, membrane (M) protein, and genomic RNA, revealing a C-terminal domain (CTD)-based assembly mechanism common among β-coronaviruses. The appearance of the N* variant within the SARS-CoV-2 B.1.1 lineage supports our conclusion that the N-terminal domain (NTD) of the N protein is not essential for viral assembly. This work not only enhances our understanding of coronavirus assembly mechanisms but also provides new insights for developing antiviral drugs targeting these conserved processes.

Efficacy of CP-COV03 (a niclosamide-based inorganic nanohybrid product) against severe fever with thrombocytopenia syndrome virus in an in vitro model.

Severe fever with thrombocytopenia syndrome (SFTS) is a tick-borne infectious disease caused by the SFTS virus (SFTSV). CP-COV03 is a novel antiviral candidate that significantly enhanced the bioavailability of niclosamide through inorganic-based drug delivery technology. The active pharmaceutical ingredient of CP-COV03, niclosamide, has been previously shown to possess broad-spectrum antiviral activity against over 30 different viruses in the in vitro tests. The aim of this study is to confirm the antiviral activity of CP-COV03 against the SFTSV in an in vitro model. Vero cells and SFTS viral stock NCCP43270, a 2015 Gangwon Province isolate, were used to obtain the 50% tissue culture infective dose of the virus. Vero cells seeded in 96-well plates were infected with SFTSV for 1 h. SFTSV-infected cells were treated with CP-COV03 at various concentrations of 0.1-100 μM and incubated for 7 days. On the seventh day of the culture, the cytopathic effect (CPE) of SFTSV was checked by microscopy and the cell viability was checked by using Cell Counting Kit-8 assay. The CPE reduced as the CP-COV03 concentration increased. The 50% inhibitory concentration (IC50) range of CP-COV03 was below 0.125 µM, as determined from the viral titers of culture supernatants collected on the third day posttreatment of CP-COV03. The plaque reduction assay showed that the IC50 of CP-COV03 was 1.893 µM, as determined from the percentage reduction of plaque counts for each drug concentration on the second day posttreatment with CP-COV03. This study suggests that CP-COV03 could be used as a potential antiviral agent for SFTS.IMPORTANCEWe demonstrated a concentration-dependent response and identified low a IC50 of CP-COV03. This result is comparable to other antiviral drugs used against viruses like severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We believe that our study makes a significant contribution to the literature as our findings suggest that CP-COV03 may serve as a potential treatment for SFTS, highlighting its importance in the field of antiviral research.

Little-known Saniculeae genera: phytochemical studies and pharmaceutical activities

AbstractThis work initiates the original and updated literature review of the current state of research on the Saniculoideae subfamily, emphasizing the selected genera Saniculeae, namely Sanicula, Hacquetia, Astrantia, and Eryngium. Various parts of these plants, especially aerial parts and roots, have an immense range of medicinal uses in traditional medicine for a number of ailments. Phytochemical studies conducted on the Saniculeae species indicate that these plants synthesize metabolites belonging to diverse groups of compounds. These include triterpenoid saponins, flavonoids, phenolic acids, coumarins, volatile organic compounds, polyacetylenes, ecdysteroids, phytosterols, lignans, betaines, carotenoids, and anthraquinones. Some of the structures of these compounds are rare in the plant kingdom. The pharmacological potential of the Saniculeae species as antioxidant, anti-inflammatory, antimicrobial, antiviral, antiprotozoal, antitumor, antidiabetic, hypocholesterolemic, and neuroprotective agents has been explored in several studies. In addition, traditional medicinal uses have been discussed to provide a comprehensive picture of this subfamily. It is known that these plants have been used to treat dermatological diseases, respiratory issues, gastrointestinal problems, inflammations, wound healing, and cancers. As far as the author is aware, this is the first study conducted on this subfamily. Therefore, this review paper is the first to examine the little-known Saniculeae genera regarding their phytochemical and pharmacological characteristics. Studies showed that Saniculeae genera synthesize distinct secondary metabolites. Therefore, further research should be conducted on the exploration of these metabolites. The pharmacological investigation should also validate their potential efficacy in treating specific ailments and support their inclusion in modern healthcare practices.

High-Throughput Insilico Drug Screen against Mpox Targeted Proteins in Comparison with Repurposed Antiviral Drugs against Natural Compounds

The recent resurgence of the Monkeypox Virus (MPXV) has prompted increased efforts to discover effective antiviral treatments. This study utilized an in silico docking approach with CB Dock2 to assess both natural compounds and repurposed antiviral medications. We concentrated on several critical viral targets for inhibition, specifically VP39 2'-O Methyltransferase, viral topoisomerase-DNA complexes, and poxin. Our results identified a number of natural substances, including Physalin A, Sitoindoside IX, Withanolide, Shatavarin 1, Kutkoside, and Berberine HCl, as promising inhibitors. Tecovirimat was found to be the most effective among the repurposed antivirals. Notably, natural products like Withanolide, Sitoindoside IX, and Physalin A showed significant inhibitory potential based on their Vina scores and binding affinities, suggesting they may serve as alternative therapeutic options. Tecovirimat consistently proved to be the most powerful inhibitor among repurposed antivirals across all examined targets, reinforcing its importance in combating MPXV.

Optimizing Patient Care through Analysis of HIV-1 Genotyping: Insights into Test Ordering Strategies, Clinical Relevance, and Implications for Managing Drug Resistance

Abstract Background Antiretroviral resistance can lead to treatment failure and disease progression, especially in HIV patients. HIV-1 sequencing/genotyping tests (e.g., GenoSure) can be ordered by clinicians to detect HIV drug resistance (HIVDR). Here, we investigated our institution’s ordering practices, clinical relevance, and rates of HIVDR. Methods A total of 94 patients positive for HIV-1 between 01/2019-08/2021 were included (n=46 pre-COVID-19 prior to 03/11/2020; n=48 post-COVID-19). Patients’ charts were reviewed for demographics, laboratory results, clinical presentation, and antiviral management. Student t-test and Fisher exact test were used for statistical analyses. Results HIV-1 genotyping was ordered most by Medicine (67%), Surgery, (7%), Emergency medicine (6%), Neurology and Obstetrics & Gynecology (5% each). Only 70% of patients with GenoSure ordered and sent out had sufficient viral loads for genotyping. Among the patients with insufficient viral loads, the GenoSure test was most ordered by Medicine (68%), Surgery (9%) and Ob/Gyn (9%) departments. Our HIV patient population was predominantly male (70%) and had a mean age of 49 years (range: 25 to 90 years). Lower viral loads (1.8x105 vs. 3.4x105 copies/mL, p=0.05), CD4 counts (174 vs. 196 cells/mcL, p=0.7), CD8 counts (555 vs. 800 cells/mcL, p=0.04), and higher CD4/CD8 ratio (0.312 vs. 0.266, p=0.57) were seen in our post-COVID-19 patients. The overall prevalence of HIVDR was 20%. There was a 9% increase in HIVDR, predominantly in non-nucleotide reverse transcriptase inhibitors (NNRTI), after the COVID-19 pandemic. For example, higher resistance was documented for antiviral drugs Efavirenz (16%), Nevirapine (16%), and Rilpivirine (13%). Increased prevalence of mutations in G190A, K101, K103, and E138 positions which confer resistance to NNRTIs was seen. The GenoSure test results helped optimize antiviral therapy in 47.8% (42/88) of total cases, with an increase of 12.5% in patients from post-COVID-19 era. Infectious disease consultations led to more actionable changes (16% increase) and ordering of the updated version of the GenoSure test that includes integrase inhibitors (20% increase, p=0.005). Conclusion We have implemented stringent clinical criteria including pathologist approval and changed our electronic health record ordering system to ensure GenoSure is appropriately ordered. Diagnostic stewardship of sequencing tests needs to be implemented to ensure actionable clinical changes in the right patient population and to control testing costs. Additionally, our findings revealed increased HIVDR in our patient population post-COVID-19. Continued surveillance and collaboration with antimicrobial stewardship are critical to managing HIVDR and improving patient outcomes, particularly given the significant strain that the COVID-19 pandemic has placed on our healthcare system.