HPMPC (cidofovir), PMEA (adefovir) and Related Acyclic Nucleoside Phosphonate Analogues: A Review of their Pharmacology and Clinical Potential in the Treatment of Viral Infections

The acyclic nucleoside phosphonate (ANP) analogues are broad-spectrum antiviral agents, with potent and selective antiviral activity in vitro and in vivo. The prototype compounds are: ( S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC, cidofovir), which is active against a wide variety of DNA viruses; 9-(2-phosphonylmethoxyethyl)adenine (PMEA, adefovir), which is active against retro-, herpes- and hepadnaviruses, and ( R)-9-(2-phosphonylmethoxypropyl) adenine (PMPA), which is active against retro- and hepadnaviruses. The antiviral action of the ANP analogues is based on a specific interaction of the active diphosphorylated metabolite with the viral DNA polymerase. The long intracellular half-life of the active metabolite accounts for the optimal efficacy in infrequent dosing schedules. The potential of HPMPC as a broad-spectrum anti-DNA virus agent, as originally observed in vitro and in vivo, has been confirmed in clinical trials. HPMPC has recently been commercially released in the USA for the treatment of cytomegalovirus retinitis in AIDS patients. In addition, topical systemic HPMPC is being (or will be) explored for use against other herpesviruses (i.e. herpes simplex virus, Epstein-Barr virus, or varicella-zoster virus), by adenoviruses, or by human papilloma- or polyomaviruses. Intravenous HPMPC is associated with dose-dependent nephrotoxicity, that should be counteracted by prehydration and concomitant administration of probenecid, and by the application of an infrequent dosing schedule. The oral prodrug of PMEA, bis(pivaloyloxymethyl)-PMEA, is currently being evaluated in patients infected with human immunodeficiency virus (HIV) or hepatitis B virus. Finally, preclinical data on the efficacy of PMPA in animal retrovirus models point to its potential usefulness against HIV infections, when given either prophylactically or therapeutically in the treatment of established HIV infections.

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Non-Toxic Virucidal Macromolecules Show High Efficacy Against Influenza Virus Ex Vivo and In Vivo

10.1101/2020.03.18.996678 ◽

2020 ◽

Author(s):

Ozgun Kocabiyik ◽

Valeria Cagno ◽

Paulo Jacob Silva ◽

Yong Zhu ◽

Laura Sedano ◽

...

Keyword(s):

Broad Spectrum ◽

Viral Infections ◽

Ex Vivo ◽

Public Health Problem ◽

Major Public Health Problem ◽

New Class ◽

Influenza Strain ◽

Low Toxicity

AbstractInfluenza is one of the most widespread viral infections worldwide and represents a major public health problem. The risk that one of the next pandemics is caused by an influenza strain is very high. It is very important to develop broad-spectrum influenza antivirals to be ready for any possible vaccine shortcomings. Anti-influenza drugs are available but they are far from ideal. Arguably, an ideal antiviral should target conserved viral domains and be virucidal, i.e. irreversibly inhibit viral infectivity. Here, we describe a new class of broad-spectrum anti-influenza macromolecules that meets these criteria and displays exceedingly low toxicity. These compounds are based on a cyclodextrin core modified on its primary face with long hydrophobic linkers terminated in 6’sialyl-N-acetyllactosamine (6’SLN) or 3’SLN. SLN enables nanomolar inhibition of the viruses while the hydrophobic linkers confer irreversibility to the inhibition. The combination of these two properties allows for efficacy in vitro against several human or avian influenza strains, as well as against a 2009 pandemic influenza strain ex vivo. Importantly, we show that, in mice, the compounds provide therapeutic efficacy when administered 24h post-infection allowing 90% survival as opposed to no survival for the placebo and oseltamivir..

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Amphipathic DNA Polymers Exhibit Antiherpetic Activity In Vitro and In Vivo

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00279-08 ◽

2008 ◽

Vol 52 (8) ◽

pp. 2727-2733 ◽

Cited By ~ 22

Author(s):

David I. Bernstein ◽

Nathalie Goyette ◽

Rhonda Cardin ◽

Earl R. Kern ◽

Guy Boivin ◽

...

Keyword(s):

Antiviral Activity ◽

Broad Spectrum ◽

Parent Compound ◽

Human Herpesvirus ◽

Varicella Zoster ◽

Barr Virus ◽

Simplex Virus ◽

Acid Stable

ABSTRACT Phosphorothioated oligonucleotides have a sequence-independent antiviral activity as amphipathic polymers (APs). The activity of these agents against herpesvirus infections in vitro and in vivo was investigated. The previously established sequence-independent, phosphorothioation-dependent antiviral activity of APs was confirmed in vitro by showing that a variety of equivalently sized homo- and heteropolymeric AP sequences were similarly active against herpes simplex virus type 1 (HSV-1) infection in vitro compared to the 40mer degenerate parent compound (REP 9), while the absence of phosphorothioation resulted in the loss of antiviral activity. In addition, REP 9 demonstrated in vitro activity against a broad spectrum of other herpesviruses: HSV-2 (50% effective concentration [EC50], 0.02 to 0.06 μM), human cytomegalovirus (EC50, 0.02 to 0.13 μM), varicella zoster virus (EC50, <0.02 μM), Epstein-Barr virus (EC50, 14.7 μM) and human herpesvirus types 6A/B (EC50, 2.9 to 10.2 μM). The murine microbicide model of genital HSV-2 was then used to evaluate in vivo activity. REP 9 (275 mg/ml) protected 75% of animals from disease and infection when provided 5 or 30 min prior to vaginal challenge. When an acid-stable analog (REP 9C) was used, 75% of mice were protected when treated with 240 mg/ml 5 min prior to infection (P < 0.001), while a lower dose (100 mg/ml) protected 100% of the mice (P < 0.001). The acid stable REP 9C formulation also provided protection at 30 min (83%, P < 0.001) and 60 min (50%, P = 0.07) against disease. These observations suggest that APs may have microbicidal activity and potential as broad-spectrum antiherpetic agents and represent a novel class of agents that should be studied further.

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Carrageenans as Broad-Spectrum Microbicides: Current Status and Challenges

Marine Drugs ◽

10.3390/md18090435 ◽

2020 ◽

Vol 18 (9) ◽

pp. 435

Author(s):

Choongho Lee

Keyword(s):

Broad Spectrum ◽

Red Algae ◽

Viral Infections ◽

Ex Vivo ◽

Antimicrobial Activities ◽

Current Status ◽

Sulfated Polysaccharides ◽

Future Research

Different kinds of red algae are enriched with chemically diverse carbohydrates. In particular, a group of sulfated polysaccharides, which were isolated from the cell walls of red algae, gained a large amount of attention due to their broad-spectrum antimicrobial activities. Within that group, carrageenans (CGs) were expected to be the first clinically applicable microbicides that could prevent various viral infections due to their superior antiviral potency and desirable safety profiles in subclinical studies. However, their anticipated beneficial effects could not be validated in human studies. To assess the value of a second attempt at pharmacologically developing CGs as a new class of preventive microbicides, all preclinical and clinical development processes of CG-based microbicides need to be thoroughly re-evaluated. In this review, the in vitro toxicities; in vivo safety profiles; and in vitro, ex vivo, and in vivo antiviral activities of CGs are summarized according to the study volume of their target viruses, which include human immunodeficiency virus, herpesviruses, respiratory viruses, human papillomavirus, dengue virus, and other viruses along with a description of their antiviral modes of action and development of antiviral resistance. This evaluation of the strengths and weaknesses of CGs will help provide future research directions that may lead to the successful development of CG-based antimicrobial prophylactics.

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Correlation between in vitro and in vivo Data of Radiolabeled Peptide for Tumor Targeting

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557519666190304120011 ◽

2019 ◽

Vol 19 (12) ◽

pp. 950-960

Author(s):

Soghra Farzipour ◽

Seyed Jalal Hosseinimehr

Keyword(s):

Tumor Targeting ◽

Single Photon ◽

Specific Binding ◽

Specific Interaction ◽

Photon Emission ◽

Emission Computed Tomography ◽

Mixed Effect ◽

Radiolabeled Peptides

Tumor-targeting peptides have been generally developed for the overexpression of tumor specific receptors in cancer cells. The use of specific radiolabeled peptide allows tumor visualization by single photon emission computed tomography (SPECT) and positron emission tomography (PET) tools. The high affinity and specific binding of radiolabeled peptide are focusing on tumoral receptors. The character of the peptide itself, in particular, its complex molecular structure and behaviors influence on its specific interaction with receptors which are overexpressed in tumor. This review summarizes various strategies which are applied for the expansion of radiolabeled peptides for tumor targeting based on in vitro and in vivo specific tumor data and then their data were compared to find any correlation between these experiments. With a careful look at previous studies, it can be found that in vitro unblock-block ratio was unable to correlate the tumor to muscle ratio and the success of radiolabeled peptide for in vivo tumor targeting. The introduction of modifiers’ approaches, nature of peptides, and type of chelators and co-ligands have mixed effect on the in vitro and in vivo specificity of radiolabeled peptides.

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Design, Synthesis, and Pharmacokinetic Evaluation of O-Carbamoyl Tizoxanide Prodrugs

Medicinal Chemistry ◽

10.2174/1573406416666201120102905 ◽

2020 ◽

Vol 16 ◽

Author(s):

Xi He ◽

Wenjun Hu ◽

Fanhua Meng ◽

Xingzhou Li

Keyword(s):

Plasma Concentration ◽

Broad Spectrum ◽

Plasma Concentrations ◽

Antiviral Drug ◽

Systemic Exposure ◽

Pharmacokinetic Profile ◽

Hydroxyl Group ◽

First Pass

Background: The broad-spectrum antiparasitic drug nitazoxanide (N) has been repositioned as a broad-spectrum antiviral drug. Nitazoxanide’s in vivo antiviral activities are mainly attributed to its metabolitetizoxanide, the deacetylation product of nitazoxanide. In reference to the pharmacokinetic profile of nitazoxanide, we proposed the hypotheses that the low plasma concentrations and the low system exposure of tizoxanide after dosing with nitazoxanide result from significant first pass effects in the liver. It was thought that this may be due to the unstable acyloxy bond of nitazoxanide. Objective: Tizoxanide prodrugs, with the more stable formamyl substituent attached to the hydroxyl group rather than the acetyl group of nitazoxanide, were designed with the thought that they might be more stable in plasma. It was anticipated that these prodrugs might be less affected by the first pass effect, which would improve plasma concentrations and system exposure of tizoxanide. Method: These O-carbamoyl tizoxanide prodrugs were synthesized and evaluated in a mouse model for pharmacokinetic (PK) properties and in an in vitro model for plasma stabilities. Results: The results indicated that the plasma concentration and the systemic exposure of tizoxanide (T) after oral administration of O-carbamoyl tizoxanide prodrugs were much greater than that produced by equimolar dosage of nitazoxanide. It was also found that the plasma concentration and the systemic exposure of tizoxanide glucuronide (TG) were much lower than that produced by nitazoxanide. Conclusion: Further analysis showed that the suitable plasma stability of O-carbamoyl tizoxanide prodrugs is the key factor in maximizing the plasma concentration and the systemic exposure of the active ingredient tizoxanide.

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Antibacterial Mechanisms and Efficacy of Sarecycline in Animal Models of Infection and Inflammation

Antibiotics ◽

10.3390/antibiotics10040439 ◽

2021 ◽

Vol 10 (4) ◽

pp. 439

Author(s):

Christopher G. Bunick ◽

Jonette Keri ◽

S. Ken Tanaka ◽

Nika Furey ◽

Giovanni Damiani ◽

...

Keyword(s):

Broad Spectrum ◽

Bacterial Resistance ◽

Antibiotic Use ◽

In Vivo Studies ◽

Infection Model ◽

Severe Acne ◽

Rat Paw Edema ◽

Infection And Inflammation

Prolonged broad-spectrum antibiotic use is more likely to induce bacterial resistance and dysbiosis of skin and gut microflora. First and second-generation tetracycline-class antibiotics have similar broad-spectrum antibacterial activity. Targeted tetracycline-class antibiotics are needed to limit antimicrobial resistance and improve patient outcomes. Sarecycline is a narrow-spectrum, third-generation tetracycline-class antibiotic Food and Drug Administration (FDA)-approved for treating moderate-to-severe acne. In vitro studies demonstrated activity against clinically relevant Gram-positive bacteria but reduced activity against Gram-negative bacteria. Recent studies have provided insight into how the structure of sarecycline, with a unique C7 moiety, interacts with bacterial ribosomes to block translation and prevent antibiotic resistance. Sarecycline reduces Staphylococcus aureus DNA and protein synthesis with limited effects on RNA, lipid, and bacterial wall synthesis. In agreement with in vitro data, sarecycline demonstrated narrower-spectrum in vivo activity in murine models of infection, exhibiting activity against S. aureus, but reduced efficacy against Escherichia coli compared to doxycycline and minocycline. In a murine neutropenic thigh wound infection model, sarecycline was as effective as doxycycline against S. aureus. The anti-inflammatory activity of sarecycline was comparable to doxycycline and minocycline in a rat paw edema model. Here, we review the antibacterial mechanisms of sarecycline and report results of in vivo studies of infection and inflammation.

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Antimalarial drugs—are they beneficial in rheumatic and viral diseases?—considerations in COVID-19 pandemic

Clinical Rheumatology ◽

10.1007/s10067-021-05805-5 ◽

2021 ◽

Author(s):

Bogna Grygiel-Górniak

Keyword(s):

Connective Tissue ◽

Viral Infections ◽

Current Knowledge ◽

Inflammatory Diseases ◽

Antiviral Drugs ◽

In Vivo Studies ◽

Viral Diseases ◽

Cardiac Complications

AbstractThe majority of the medical fraternity is continuously involved in finding new therapeutic schemes, including antimalarial medications (AMDs), which can be useful in combating the 2019-nCoV: coronavirus disease (COVID-19). For many decades, AMDs have been widely used in the treatment of malaria and various other anti-inflammatory diseases, particularly to treat autoimmune disorders of the connective tissue. The review comprises in vitro and in vivo studies, original studies, clinical trials, and consensus reports for the analysis, which were available in medical databases (e.g., PubMed). This manuscript summarizes the current knowledge about chloroquine (CQ)/hydroxychloroquine (HCQ) and shows the difference between their use, activity, recommendation, doses, and adverse effects on two groups of patients: those with rheumatic and viral diseases (including COVID-19). In the case of connective tissue disorders, AMDs are prescribed for a prolonged duration in small doses, and their effect is observed after few weeks, whereas in the case of viral infections, they are prescribed in larger doses for a short duration to achieve a quick saturation effect. In rheumatic diseases, AMDs are well tolerated, and their side effects are rare. However, in some viral diseases, the effect of AMDs is questionable or not so noticeable as suggested during the initial prognosis. They are mainly used as an additive therapy to antiviral drugs, but recent studies have shown that AMDs can diminish the efficacy of some antiviral drugs and may cause respiratory, kidney, liver, and cardiac complications.

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Effect of Coxsackievirus B4 Infection on the Thymus: Elucidating Its Role in the Pathogenesis of Type 1 Diabetes

Microorganisms ◽

10.3390/microorganisms9061177 ◽

2021 ◽

Vol 9 (6) ◽

pp. 1177

Author(s):

Abdulaziz Alhazmi ◽

Magloire Pandoua Nekoua ◽

Hélène Michaux ◽

Famara Sane ◽

Aymen Halouani ◽

...

Keyword(s):

Type 1 Diabetes ◽

T Cell ◽

Viral Infections ◽

Lymphoid Organ ◽

Thymic Epithelial Cells ◽

Central Tolerance ◽

Coxsackievirus B4

The thymus gland is a primary lymphoid organ for T-cell development. Various viral infections can result in disturbance of thymic functions. Medullary thymic epithelial cells (mTECs) are important for the negative selection of self-reactive T-cells to ensure central tolerance. Insulin-like growth factor 2 (IGF2) is the dominant self-peptide of the insulin family expressed in mTECs and plays a crucial role in the intra-thymic programing of central tolerance to insulin-secreting islet β-cells. Coxsackievirus B4 (CVB4) can infect and persist in the thymus of humans and mice, thus hampering the T-cell maturation and differentiation process. The modulation of IGF2 expression and protein synthesis during a CVB4 infection has been observed in vitro and in vivo in mouse models. The effect of CVB4 infections on human and mouse fetal thymus has been studied in vitro. Moreover, following the inoculation of CVB4 in pregnant mice, the thymic function in the fetus and offspring was disturbed. A defect in the intra-thymic expression of self-peptides by mTECs may be triggered by CVB4. The effects of viral infections, especially CVB4 infection, on thymic cells and functions and their possible role in the pathogenesis of type 1 diabetes (T1D) are presented.

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