Discovery of broad-spectrum antivirals targeting viral proteases using in silico structural modeling and cellular analysis.

The development of broad-spectrum antivirals is a high-priority goal to prevent future global outbreaks. Some antiviral agents developed for specific viral protein targets may exhibit broad-spectrum antiviral activity or provide helpful information for broad-spectrum drug development. In this study, we compared the sequence- and structure-based similarity of SARS-CoV-2 3CL with proteases from other viruses and identified 24 proteases with similar active-site structures.

Combating yellow fever virus with 7-deaza-7-fluoro-2'-C-methyladenosine.

Yellow fever virus (YFV) is a deadly zoonotic flavivirus endemic in tropical/sub-tropical Africa and South America transmitted by mosquito vector (; ) to humans and non-human primates. There are no approved antiviral agents for YFV. We previously identified 7-deaza-7-fluoro-2'-C-methyladenosine (DFA) with anti-YFV activity.

Sustained antiviral insulin signaling during West Nile virus infection results in viral mutations.

Arthropod-borne viruses or arboviruses, including West Nile virus (WNV), dengue virus (DENV), and Zika virus (ZIKV) pose significant threats to public health. It is imperative to develop novel methods to control these mosquito-borne viral infections. We previously showed that insulin/insulin-like growth factor-1 signaling (IIS)-dependent activation of ERK and JAK-STAT signaling has significant antiviral activity in insects and human cells.

Why Certain Repurposed Drugs Are Unlikely to Be Effective Antivirals to Treat SARS-CoV-2 Infections.

Most repurposed drugs have proved ineffective for treating COVID-19. We evaluated median effective and toxic concentrations (EC, CC) of 49 drugs, mostly from previous clinical trials, in Vero cells. Ratios of reported unbound peak plasma concentrations, (C)/EC, were used to predict the potential in vivo efficacy.

Exploring the relationship between flumethrin resistance and Anaplasma marginale infection in Rhipicephalus (Boophilus) microplus ticks of cattle.

The study explores the relationship between flumethrin resistance and Anaplasma marginale infection in Rhipicephalus (Boophilus) microplus of cattle in South Gujarat, India. Adult Immersion Test (AIT) was used to assess flumethrin resistance and polymerase chain reaction (PCR) to confirm A. marginale infection.

Synthesis and biological evaluation of novel peptidomimetic inhibitors of the coronavirus 3C-like protease.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and related variants, are responsible for the devastating coronavirus disease 2019 (COVID-19) pandemic. The SARS-CoV-2 main protease (Mpro) plays a central role in the replication of the virus and represents an attractive drug target. Herein, we report the discovery of novel SARS-CoV-2 Mpro covalent inhibitors, including highly effective compound NIP-22c which displays high potency against several key variants and clinically relevant nirmatrelvir Mpro E166V mutants.

Synthesis and evaluation of highly potent HBV capsid assembly modulators (CAMs).

Chronic hepatitis B virus (HBV) infection remains a major global health burden. It affects more than 290 million individuals worldwide and is responsible for approximately 900,000 deaths annually. Anti-HBV treatment with a nucleoside analog in combination with pegylated interferon are considered first-line therapy for patients with chronic HBV infection and liver inflammation.

The premise of capsid assembly modulators towards eliminating HBV persistence.

Introduction: The burden of chronic hepatitis B virus (HBV) results in almost a million deaths per year. The most common treatment for chronic hepatitis B infection is long-term nucleoside analogs (NUC) or one-year interferon-alpha (pegylated or non-pegylated) therapy before or after NUC therapy. Unfortunately, these therapies rarely result in HBV functional cure because they do not eradicate HBV from the nucleus of the hepatocytes, where the covalently closed circular DNA (cccDNA) is formed and/or where the integrated HBV DNA persists in the host genome.

Discovery of a 2'-Fluoro,2'-Bromouridine Phosphoramidate Prodrug Exhibiting Anti-Yellow Fever Virus Activity in Culture and in Mice.

Yellow fever virus (YFV) is a potentially lethal, zoonotic, blood-borne flavivirus transmitted to humans and non-human primates by mosquitoes. Owing to multiple deadly epidemics, the WHO classifies YFV as a "high impact, high threat disease" with resurgent epidemic potential. At present, there are no approved antiviral therapies to combat YFV infection.

Assessment of a Computational Approach to Predict Drug Resistance Mutations for HIV, HBV and SARS-CoV-2.

Viral resistance is a worldwide problem mitigating the effectiveness of antiviral drugs. Mutations in the drug-targeting proteins are the primary mechanism for the emergence of drug resistance. It is essential to identify the drug resistance mutations to elucidate the mechanism of resistance and to suggest promising treatment strategies to counter the drug resistance.

An EvoDevo Study of Salmonid Visual Opsin Dynamics and Photopigment Spectral Sensitivity.

Salmonids are ideal models as many species follow a distinct developmental program from demersal eggs and a large yolk sac to hatching at an advanced developmental stage. Further, these economically important teleosts inhabit both marine- and freshwaters and experience diverse light environments during their life histories. At a genome level, salmonids have undergone a salmonid-specific fourth whole genome duplication event (Ss4R) compared to other teleosts that are already more genetically diverse compared to many non-teleost vertebrates.

HIV nucleoside reverse transcriptase inhibitors.

More than 40 years into the pandemic, HIV remains a global burden and as of now, there is no cure in sight. Fortunately, highly active antiretroviral therapy (HAART) has been developed to manage and suppress HIV infection. Combinations of two to three drugs targeting key viral proteins, including compounds inhibiting HIV reverse transcriptase (RT), have become the cornerstone of HIV treatment.

The best backbone for HIV prevention, treatment, and elimination: Emtricitabine+tenofovir.

The advent of antiretroviral combination therapy has significantly impacted the HIV/AIDS epidemic. No longer a death sentence, HIV infection can be controlled and suppressed using cocktail therapies that contain two or more small molecule drugs. This review aims to highlight the discovery, development, and impact of one such molecule, namely, emtricitabine (FTC, emtriva), which is one of the most successful drugs in the fight against HIV/AIDS and has been taken by over 94% of individuals infected with HIV in the USA.

In silico design of a novel nucleotide antiviral agent by free energy perturbation.

Nucleoside analogs are the backbone of antiviral therapies. Drugs from this class undergo processing by host or viral kinases to form the active nucleoside triphosphate species that selectively inhibits the viral polymerase. It is the central hypothesis that the nucleoside triphosphate analog must be a favorable substrate for the viral polymerase and the nucleoside precursor must be a satisfactory substrate for the host kinases to inhibit viral replication.

The Mechanism of Action of Hepatitis B Virus Capsid Assembly Modulators Can Be Predicted from Binding to Early Assembly Intermediates.

Interfering with the self-assembly of virus nucleocapsids is a promising approach for the development of novel antiviral agents. Applied to hepatitis B virus (HBV), this approach has led to several classes of capsid assembly modulators (CAMs) that target the virus by either accelerating nucleocapsid assembly or misdirecting it into noncapsid-like particles, thereby inhibiting the HBV replication cycle. Here, we have assessed the structures of early nucleocapsid assembly intermediates, bound with and without CAMs, using molecular dynamics simulations.

Paired Simulations and Experimental Investigations into the Calcium-Dependent Conformation of Albumin.

Serum albumin is the most abundant protein in blood plasma, and it is involved in multiple biological processes. Serum albumin has recently been adapted for improving biomaterial integration with bone tissue, and studies have shown the importance of this protein in bone repair and regeneration. However, the mechanism of action is not yet clear.

Contemporary Approaches to the Discovery and Development of Broad-Spectrum Natural Product Prototypes for the Control of Coronaviruses.

The pressing need for SARS-CoV-2 controls has led to a reassessment of strategies to identify and develop natural product inhibitors of zoonotic, highly virulent, and rapidly emerging viruses. This review article addresses how contemporary approaches involving computational chemistry, natural product (NP) and protein databases, and mass spectrometry (MS) derived target-ligand interaction analysis can be utilized to expedite the interrogation of NP structures while minimizing the time and expense of extraction, purification, and screening in BioSafety Laboratories (BSL)3 laboratories. The unparalleled structural diversity and complexity of NPs is an extraordinary resource for the discovery and development of broad-spectrum inhibitors of viral genera, including , which contains MERS, SARS, SARS-CoV-2, and the common cold.

Implementing and Assessing an Alchemical Method for Calculating Protein-Protein Binding Free Energy.

Protein-protein binding is fundamental to most biological processes. It is important to be able to use computation to accurately estimate the change in protein-protein binding free energy due to mutations in order to answer biological questions that would be experimentally challenging, laborious, or time-consuming. Although nonrigorous free-energy methods are faster, rigorous alchemical molecular dynamics-based methods are considerably more accurate and are becoming more feasible with the advancement of computer hardware and molecular simulation software.

DHFR and DHPS Mutations Are Associated With HIV-1 Co-Infection and a Novel DHPS Mutation I504T Is Identified in Western Kenya.

Antifolate resistance is significant in Kenya and presumed to result from extensive use and cross-resistance between antifolate antimalarials and antibiotics, including cotrimoxazole/Bactrim used for HIV-1 chemotherapy. However, little is known about antifolate-resistant malaria in the context of newly diagnosed HIV-1 co-infection prior to administration of HIV-1 chemotherapy. Blood samples from a cross-sectional study of asymptomatic adult Kenyans enrolled during voluntary HIV testing were analyzed by PCR for spp.

Short-wavelength-sensitive 2 (Sws2) visual photopigment models combined with atomistic molecular simulations to predict spectral peaks of absorbance.

For many species, vision is one of the most important sensory modalities for mediating essential tasks that include navigation, predation and foraging, predator avoidance, and numerous social behaviors. The vertebrate visual process begins when photons of the light interact with rod and cone photoreceptors that are present in the neural retina. Vertebrate visual photopigments are housed within these photoreceptor cells and are sensitive to a wide range of wavelengths that peak within the light spectrum, the latter of which is a function of the type of chromophore used and how it interacts with specific amino acid residues found within the opsin protein sequence.

Modulation of Lymphocyte Potassium Channel K1.3 by Membrane-Penetrating, Joint-Targeting Immunomodulatory Plant Defensin.

We describe a cysteine-rich, membrane-penetrating, joint-targeting, and remarkably stable peptide, EgK5, that modulates voltage-gated K1.3 potassium channels in T lymphocytes by a distinctive mechanism. EgK5 enters plasma membranes and binds to K1.

Structural Determinants Mediating Tertiapin Block of Neuronal Kir3.2 Channels.

Tertiapin (TPN) is a 21 amino acid venom peptide from that inhibits certain members of the inward rectifier potassium (Kir) channel family at a nanomolar affinity with limited specificity. Structure-based computational simulations predict that TPN behaves as a pore blocker; however, the molecular determinants mediating block of neuronal Kir3 channels have been inconclusive and unvalidated. Here, using molecular docking and molecular dynamics (MD) simulations with 'potential of mean force' (PMF) calculations, we investigated the energetically most favored interaction of TPN with several Kir3.

The histone acetyltransferase inhibitor Nir regulates epidermis development.

In addition to its function as an inhibitor of histone acetyltransferases, Nir (Noc2l) binds to p53 and TAp63 to regulate their activity. Here, we show that epidermis-specific ablation of Nir impairs epidermal stratification and barrier function, resulting in perinatal lethality. Nir-deficient epidermis lacks appendages and remains single layered during embryogenesis.