Antiviral Activity of Arabinosylthymine in Herpesviral Replication: Mechanism of Action In Vivo and In Vitro

AbstractMicrotubules (MTs) are structural units in the cytoskeleton. In brain cells they are responsible for axonal transport, information processing, and signaling mechanisms. Proper function of these processes is critical for healthy brain functions. Alcohol and substance use disorders (AUD/SUDs) affects the function and organization of MTs in the brain, making them a potential neuroimaging marker to study the resulting impairment of overall neurobehavioral and cognitive processes. Our lab reported the first brain-penetrant MT-tracking Positron Emission Tomography (PET) ligand [11C]MPC-6827 and demonstrated its in vivo utility in rodents and non-human primates. To further explore the in vivo imaging potential of [11C]MPC-6827, we need to investigate its mechanism of action. Here, we report preliminary in vitro binding results in SH-SY5Y neuroblastoma cells exposed to ethanol (EtOH) or cocaine in combination with multiple agents that alter MT stability. EtOH and cocaine treatments increased MT stability and decreased free tubulin monomers. Our initial cell-binding assay demonstrated that [11C]MPC-6827 may have high affinity to free/unbound tubulin units. Consistent with this mechanism of action, we observed lower [11C]MPC-6827 uptake in SH-SY5Y cells after EtOH and cocaine treatments (e.g., fewer free tubulin units). We are currently performing in vivo PET imaging and ex vivo biodistribution studies in rodent and nonhuman primate models of AUD and SUDs and Alzheimer's disease.

Download Full-text

Antiviral activity of Mulberroside C against enterovirus A71 in vitro and in vivo

European Journal of Pharmacology ◽

10.1016/j.ejphar.2021.174204 ◽

2021 ◽

pp. 174204

Author(s):

Yiming Cao ◽

En Lei ◽

Lei Li ◽

Jin Ren ◽

Xiaoyang He ◽

...

Keyword(s):

Antiviral Activity ◽

Enterovirus A71

Download Full-text

Filociclovir Is an Active Antiviral Agent against Ocular Adenovirus Isolates In Vitro and in the Ad5/NZW Rabbit Ocular Model

Pharmaceuticals ◽

10.3390/ph14040294 ◽

2021 ◽

Vol 14 (4) ◽

pp. 294

Author(s):

Eric G. Romanowski ◽

Islam T. M. Hussein ◽

Steven C. Cardinale ◽

Michelle M. Butler ◽

Lucas R. Morin ◽

...

Keyword(s):

Antiviral Activity ◽

Topical Treatment ◽

Antiviral Agent ◽

Human Adenovirus ◽

Treatment Groups ◽

Ocular Infections ◽

The Mean ◽

Eye Infection

Presently, there is no FDA- or EMA-approved antiviral for the treatment of human adenovirus (HAdV) ocular infections. This study determined the antiviral activity of filociclovir (FCV) against ocular HAdV isolates in vitro and in the Ad5/NZW rabbit ocular model. The 50% effective concentrations (EC50) of FCV and cidofovir (CDV) were determined for several ocular HAdV types using standard plaque reduction assays. Rabbits were topically inoculated in both eyes with HAdV5. On day 1, the rabbits were divided into four topical treatment groups: (1) 0.5% FCV 4x/day × 10 d; (2) 0.1% FCV 4x/day × 10 d; (3) 0.5% CDV 2x/day × 7 d; (4) vehicle 4x/day × 10 d. Eyes were cultured for virus on days 0, 1, 3, 4, 5, 7, 9, 11, and 14. The resulting viral eye titers were determined using standard plaque assays. The mean in vitro EC50 for FCV against tested HAdV types ranged from 0.50 to 4.68 µM, whereas those treated with CDV ranged from 0.49 to 30.3 µM. In vivo, compared to vehicle, 0.5% FCV, 0.1% FCV, and 0.5% CDV produced lower eye titers, fewer numbers of positive eye cultures, and shorter durations of eye infection. FCV demonstrated anti-adenovirus activity in vitro and in vivo.

Download Full-text

Possible Future Monoclonal Antibody (mAb)-Based Therapy against Arbovirus Infections

BioMed Research International ◽

10.1155/2013/838491 ◽

2013 ◽

Vol 2013 ◽

pp. 1-21 ◽

Cited By ~ 12

Author(s):

Giuseppe Sautto ◽

Nicasio Mancini ◽

Giacomo Gorini ◽

Massimo Clementi ◽

Roberto Burioni

Keyword(s):

Monoclonal Antibody ◽

Monoclonal Antibodies ◽

Side Effects ◽

Antiviral Activity ◽

The Other ◽

Viral Escape ◽

Passive Immunotherapy ◽

Medical Need

More than 150 arboviruses belonging to different families are known to infect humans, causing endemic infections as well as epidemic outbreaks. Effective vaccines to limit the occurrence of some of these infections have been licensed, while for the others several new immunogens are under development mostly for their improvements concerning safety and effectiveness profiles. On the other hand, specific and effective antiviral drugs are not yet available, posing an urgent medical need in particular for emergency cases. Neutralizing monoclonal antibodies (mAbs) have been demonstrated to be effective in the treatment of several infectious diseases as well as in preliminaryin vitroandin vivomodels of arbovirus-related infections. Given their specific antiviral activity as well-tolerated molecules with limited side effects, mAbs could represent a new therapeutic approach for the development of an effective treatment, as well as useful tools in the study of the host-virus interplay and in the development of more effective immunogens. However, before their use as candidate therapeutics, possible hurdles (e.g., Ab-dependent enhancement of infection, occurrence of viral escape variants) must be carefully evaluated. In this review are described the main arboviruses infecting humans and candidate mAbs to be possibly used in a future passive immunotherapy.

Download Full-text

Template-dependent biosynthesis of poly(G)·poly(C) and its antiviral activity in vitro and in vivo

Antiviral Research ◽

10.1016/s0166-3542(98)00018-7 ◽

1998 ◽

Vol 38 (2) ◽

pp. 131-140 ◽

Cited By ~ 1

Author(s):

M.A Surzhik ◽

L.M Vilner ◽

A.L Katchurin ◽

A.L Timkovskii

Keyword(s):

Antiviral Activity

Download Full-text

Bacteriophage-derived CHAP domain protein, P128, kills Staphylococcus cells by cleaving interpeptide cross-bridge of peptidoglycan

Microbiology ◽

10.1099/mic.0.079111-0 ◽

2014 ◽

Vol 160 (10) ◽

pp. 2157-2169 ◽

Cited By ~ 13

Author(s):

Sudarson Sundarrajan ◽

Junjappa Raghupatil ◽

Aradhana Vipra ◽

Nagalakshmi Narasimhaswamy ◽

Sanjeev Saravanan ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Mechanism Of Action ◽

Catalytic Domain ◽

Antibiotic Sensitivity ◽

High Sensitivity ◽

Common Mechanism ◽

Cross Bridge ◽

Sensitivity Pattern

P128 is an anti-staphylococcal protein consisting of the Staphylococcus aureus phage-K-derived tail-associated muralytic enzyme (TAME) catalytic domain (Lys16) fused with the cell-wall-binding SH3b domain of lysostaphin. In order to understand the mechanism of action and emergence of resistance to P128, we isolated mutants of Staphylococcus spp., including meticillin-resistant Staphylococcus aureus (MRSA), resistant to P128. In addition to P128, the mutants also showed resistance to Lys16, the catalytic domain of P128. The mutants showed loss of fitness as shown by reduced rate of growth in vitro. One of the mutants tested was found to show reduced virulence in animal models of S. aureus septicaemia suggesting loss of fitness in vivo as well. Analysis of the antibiotic sensitivity pattern showed that the mutants derived from MRSA strains had become sensitive to meticillin and other β-lactams. Interestingly, the mutant cells were resistant to the lytic action of phage K, although the phage was able to adsorb to these cells. Sequencing of the femA gene of three P128-resistant mutants showed either a truncation or deletion in femA, suggesting that improper cross-bridge formation in S. aureus could be causing resistance to P128. Using glutathione S-transferase (GST) fusion peptides as substrates it was found that both P128 and Lys16 were capable of cleaving a pentaglycine sequence, suggesting that P128 might be killing S. aureus by cleaving the pentaglycine cross-bridge of peptidoglycan. Moreover, peptides corresponding to the reported cross-bridge of Staphylococcus haemolyticus (GGSGG, AGSGG), which were not cleaved by lysostaphin, were cleaved efficiently by P128. This was also reflected in high sensitivity of S. haemolyticus to P128. This showed that in spite of sharing a common mechanism of action with lysostaphin, P128 has unique properties, which allow it to act on certain lysostaphin-resistant Staphylococcus strains.

Download Full-text