First-in-human trial evaluating safety and pharmacokinetics of AT-752, a novel nucleotide prodrug with pan-serotype activity against dengue virus.

AT-752 is a novel guanosine nucleotide prodrug inhibitor of the dengue virus (DENV) polymerase with sub-micromolar, pan-serotype antiviral activity. This phase 1, double-blind, placebo-controlled, first-in-human study evaluated the safety, tolerability, and pharmacokinetics of ascending single and multiple oral doses of AT-752 in healthy subjects. AT-752 was well tolerated when administered as a single dose up to 1,500 mg or when administered as multiple doses up to 750 mg three times daily (TID). No serious adverse events occurred, and the majority of treatment-emergent adverse events were mild in severity and resolved by the end of the study. In those receiving single ascending doses of AT-752, no pharmacokinetic sensitivity was observed in Asian subjects, and no food effect was observed. Plasma exposure of the guanosine nucleoside metabolite AT-273, the surrogate of the active triphosphate metabolite of the drug, increased with increasing dose levels of AT-752 and exhibited a long half-life of approximately 15-25 h. Administration of AT-752 750 mg TID led to a rapid increase in plasma levels of AT-273 exceeding the target in vitro 90% effective concentration (EC90) of 0.64 µM in inhibiting DENV replication, and maintained this level over the treatment period. The favorable safety and pharmacokinetic results support the evaluation of AT-752 as an antiviral for the treatment of dengue in future clinical studies.Registered at ClinicalTrials.gov (NCT04722627).

Human bronchopulmonary disposition and plasma pharmacokinetics of oral bemnifosbuvir (AT-527), an experimental guanosine nucleotide prodrug for COVID-19.

BACKGROUND: Bemnifosbuvir (AT-527) is a novel oral guanosine nucleotide antiviral drug for the treatment of persons with COVID-19. Direct assessment of drug disposition in the lungs, via bronchoalveolar lavage, is necessary to ensure antiviral drug levels at the primary site of SARS-CoV-2 infection are achieved. OBJECTIVES: This Phase 1 study in healthy subjects aimed to assess the bronchopulmonary pharmacokinetics, safety and tolerability of repeated doses of bemnifosbuvir. METHODS: A total of 24 subjects were assigned to receive bemnifosbuvir twice daily at doses of 275, 550 or 825 mg for up to 3.5 days. RESULTS: AT-511, the free base of bemnifosbuvir, was largely eliminated from the plasma within 6 h post dose in all dosing groups. Antiviral drug levels of bemnifosbuvir were consistently achieved in the lungs with bemnifosbuvir 550 mg twice daily. The mean level of the guanosine nucleoside metabolite AT-273, the surrogate of the active triphosphate metabolite of the drug, measured in the epithelial lining fluid of the lungs was 0.62 µM at 4-5 h post dose. This exceeded the target in vitro 90% effective concentration (EC90) of 0.5 µM for antiviral drug exposure against SARS-CoV-2 replication in human airway epithelial cells. Bemnifosbuvir was well tolerated across all doses tested, and most treatment-emergent adverse events reported were mild in severity and resolved. CONCLUSIONS: The favourable pharmacokinetics and safety profile of bemnifosbuvir demonstrates its potential as an oral antiviral treatment for COVID-19, with 550 mg bemnifosbuvir twice daily currently under further clinical evaluation in persons with COVID-19.

Organocatalyzed asymmetric dearomative 1,3-dipolar cycloaddition of 2-nitrobenzofurans and N-2,2,2-trifluoroethylisatin ketimines.

A readily available chiral cyclohexanediamine-derived bifunctional tertiary amine-squaramide catalyst is more effective for the asymmetric dearomative 1,3-dipolar cycloaddition of 2-nitrobenzofurans and N-2,2,2-trifluoroethylisatin ketimines. A range of structurally diverse spiro-fused polyheterocyclic compounds containing oxindole, pyrrolidine, and hydrobenzofuran motifs were smoothly obtained in excellent results (up to 99% yield, >20:1 dr in all cases and up to 99% ee). This method features high efficiency, mild reaction conditions, exquisite asymmetric induction, wide functional group tolerance, great potential for scale-up synthesis, and attractive product diversification.

The relationship between vitamin D levels in umbilical cord blood and infantile eczema.

A total of 179 normal full-term pregnant women and their newborns were randomly selected. Umbilical venous blood was extracted after the delivery, and the serum level of 25(OH)D3 was measured. Forty 2 days, 3 months, 6 months, and one year after the birth to be asked about the occurrence and development of infant eczema. Thirteen cases were lost to follow-up. The median concentration of 25(OH)D3 in the cord blood was 25.40 ng/mL. Thirty eight cases (22.9%) were vitamin D deficient (<20 ng/mL), 77 cases (46.4%) were vitamin D insufficient (20-30 ng/mL), and 51 cases (30.7%) were vitamin D sufficient (≥30 ng/mL). The incidence of eczema in the umbilical cord blood vitamin D sufficient group was lower than that in the deficient and insufficient groups (p < .05). Sufficient umbilical cord blood vitamin D levels are associated with a lower incidence of eczema in infants up to one year of age. IMPACT STATEMENTWhat is already known on this subject? A number of studies have suggested that vitamin D levels in early life are related to the occurrence of allergic diseases, but the conclusions are not uniform.What do the results of this study add? The rate of sufficient umbilical cord blood vitamin D was low in the Songjiang area of Shanghai. Sufficient umbilical cord blood vitamin D levels (≥30 ng/mL) are associated with a lower incidence of eczema in infants up to 1 year of age.What are the implications of these findings for clinical practice and/or further research? At present, the dose of vitamin D for pregnant women at home and abroad is not consistent, so the specific dose of vitamin D for pregnant women to maintain the foetus needs further discussion. It is expected that a reasonable recommended dose can be developed to reduce the risk of allergic diseases in future generations from a primary prevention perspective.

AT-527, a Double Prodrug of a Guanosine Nucleotide Analog, Is a Potent Inhibitor of SARS-CoV-2 In Vitro and a Promising Oral Antiviral for Treatment of COVID-19.

The impact of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of COVID-19, is global and unprecedented. Although remdesivir has recently been approved by the FDA to treat SARS-CoV-2 infection, no oral antiviral is available for outpatient treatment. AT-527, an orally administered double prodrug of a guanosine nucleotide analog, was previously shown to be highly efficacious and well tolerated in hepatitis C virus (HCV)-infected subjects. Here, we report the potent in vitro activity of AT-511, the free base of AT-527, against several coronaviruses, including SARS-CoV-2. In normal human airway epithelial cells, the concentration of AT-511 required to inhibit replication of SARS-CoV-2 by 90% (EC90) was 0.47 µM, very similar to its EC90 against human coronavirus (HCoV)-229E, HCoV-OC43, and SARS-CoV in Huh-7 cells. Little to no cytotoxicity was observed for AT-511 at concentrations up to 100 µM. Substantial levels of the active triphosphate metabolite AT-9010 were formed in normal human bronchial and nasal epithelial cells incubated with 10 µM AT-511 (698 ± 15 and 236 ± 14 µM, respectively), with a half-life of at least 38 h. Results from steady-state pharmacokinetic and tissue distribution studies of nonhuman primates administered oral doses of AT-527, as well as pharmacokinetic data from subjects given daily oral doses of AT-527, predict that twice daily oral doses of 550 mg AT-527 will produce AT-9010 trough concentrations in human lung that exceed the EC90 observed for the prodrug against SARS-CoV-2 replication. This suggests that AT-527 may be an effective treatment option for COVID-19.

Safety, pharmacokinetics and antiviral activity of AT-527, a novel purine nucleotide prodrug, in HCV-infected subjects with and without cirrhosis.

AT-527 is a novel modified guanosine nucleotide prodrug inhibitor of the hepatitis C virus (HCV) NS5B polymerase, with increased in vitro antiviral activity as compared to sofosbuvir and a highly differentiated favorable preclinical profile compared to other anti-HCV nucleoside/nucleotide analogs. This was a multiple part clinical study where multiple ascending doses of AT-527 up to 600 mg (expressed as AT-527 salt form; equivalent to 553 mg free base) once daily for seven days were evaluated in a randomized, double-blind, placebo-controlled study of treatment-naïve, non-cirrhotic, genotype 1b, HCV-infected subjects. The highest dose of AT-527 for the same duration was then evaluated in two open label cohorts of a) non-cirrhotic, genotype 3, HCV-infected subjects and b) HCV-infected subjects of any genotype with compensated (Child-Pugh A) cirrhosis. AT-527 was well tolerated for seven days in all cohorts. At the highest dose tested, mean HCV RNA reductions of up to 2.4 log10 IU/mL occurred within the first 24 hours of dosing. Mean maximum reductions observed with seven days of dosing were 4.4, 4.5 and 4.6 log10 IU/mL in non-cirrhotic subjects with HCV genotype 1b, non-cirrhotic subjects with HCV genotype 3, and subjects with compensated cirrhosis, respectively. The systemic half-life of AT-273, the nucleoside metabolite considered a surrogate of intracellular phosphates including the active triphosphate, exceeded 20 hours, supporting once daily dosing. In summary, AT-527 demonstrated rapid, potent, dose/exposure-related and pan-genotypic antiviral activity with similar responses between subjects with and without cirrhosis. Exposure-antiviral response analysis identified 550 mg (free base equivalent) as the optimal dose of AT-527. Safety and antiviral activity data from this study warrant continued clinical development of AT-527 dosed once daily.

Organocatalyzed Asymmetric Dearomative Aza-Michael/Michael Addition Cascade of 2-Nitrobenzofurans and 2-Nitrobenzothiophenes with 2-Aminochalcones.

An organocatalyzed dearomative aza-Michael/Michael addition cascade of 2-nitrobenzofurans and 2-nitrobenzothiophenes with 2-aminochalcones has been developed, opening a new channel to access a series of optically active tetrahydrobenzofuro[3,2- b]quinolines and tetrahydrobenzo[4,5]thieno[3,2- b]quinolines bearing three contiguous stereocenters with excellent diastereo- and enantioselectivities (all cases >20:1 dr, up to 99% ee). This study features the first asymmetric dearomative cascade reaction of 2-nitrobenzofurans and 2-nitrobenzothiophenes beginning with aza-Michael addition. The potential applications of the methodology were demonstrated by the preparative-scale experiment and the versatile transformations of the products.

NaBr-Induced Production of Brominated Azaphilones and Related Tricyclic Polyketides by the Marine-Derived Fungus Penicillium janthinellum HK1-6.

Cultivation of the mangrove rhizosphere soil-derived fungus Penicillium janthinellum HK1-6 with NaBr led to the isolation of two new brominated azaphilones, penicilones G and H (5, 6), two new tricyclic polyketides, penijanthinones A and B (7, 8), and two known azaphilones, penicilones A and B (1, 2). The planar structures and relative configurations of the new compounds were elucidated using comprehensive spectroscopic methods including 1D and 2D NOE spectra. Their absolute configurations were determined by chemical conversions, TDDFT ECD calculations, and comparisons of their ECD spectra. Interestingly, the NaBr-induced brominated azaphilones (5, 6) had the opposite configuration at C-7 compared to the chloro analogues (3, 4) produced by this fungus cultivated with sea salt. Ester hydrolysis of penicilone B (2) afforded the carboxylic acid side chain 2,4-dimethyldec-2-enoic acid (9), with a 4 S configuration assigned by its specific rotation. Penicilone H (6) showed antibacterial activity with MIC values ranging from 3.13 to 12.5 µg/mL.

New Naphtho-γ-Pyrones Isolated from Marine-Derived Fungus Penicillium sp. HK1-22 and Their Antimicrobial Activities.

Three novel monomeric naphtho-γ-pyrones, peninaphones A-C (compounds 1-3), along with two known bis-naphtho-γ-pyrones (compounds 4 and 5) were isolated from mangrove rhizosphere soil-derived fungus Penicillium sp. HK1-22. The absolute configurations of compounds 1 and 2 were determined by electronic circular dichroism (ECD) spectra, and the structure of compound 3 was confirmed by single-crystal X-ray diffraction analysis. Compounds 4 and 5 are a pair of hindered rotation isomers. A hypothetical biosynthetic pathway for the isolated monomeric and dimeric naphtho-γ-pyrones is also discussed in this study. Compounds 1-3 showed antibacterial activity against Staphylococcus aureus (ATCC 43300, 33591, 29213, and 25923) with minimum inhibitory concentration (MIC) values in the range of 12.5-50 µg/mL. Compound 3 exhibited significant activity against the rice sheath blight pathogen Rhizoctonia solani.

A randomized, double-blind, multiple-dose study of the pan-genotypic NS5A inhibitor samatasvir in patients infected with hepatitis C virus genotype 1, 2, 3 or 4.

BACKGROUND & AIMS: Samatasvir is a pan-genotypic inhibitor of the hepatitis C (HCV) non-structural protein 5A (NS5A). This study evaluated the antiviral activity, pharmacokinetics and safety of samatasvir monotherapy in treatment-naïve subjects infected with HCV genotype 1-4. METHODS: Thirty-four genotype 1 and thirty genotype 2, 3 or 4 subjects were randomized to receive for 3days placebo or samatasvir 25-100mg per day. Plasma samples for HCV RNA, pharmacokinetics and sequencing were collected up to day 10. RESULTS: Samatasvir achieved potent antiviral activity across genotypes: mean maximum reductions from baseline were 3.2-3.6 (genotype 1a), 3.0-4.3 (genotype 1b), 3.2-3.4 (genotype 3), and 3.6-3.9 (genotype 4) log10/ml respectively; no viral rebound was observed during the 3-day treatment period. For genotype 2 HCV, samatasvir was active in subjects with NS5A L31 polymorphism at baseline (individual range 2.5-4.1 log10/ml), but showed minimal activity in those with baseline M31 polymorphism. Samatasvir exhibited a long plasma half-life of approximately 20h which supports once daily dosing. Samatasvir was well tolerated in all subjects with no safety-related discontinuations or serious adverse events. The most common adverse events included constipation, nausea and headache and occurred at similar frequency in active and placebo subjects. All events were mild or moderate in intensity. There were no patterns or dose dependence of adverse events, vital signs, laboratory parameters or electrocardiograms. CONCLUSIONS: Samatasvir 25-100mg monotherapy for 3days was well tolerated and induced a rapid and profound reduction in plasma HCV RNA in subjects infected with HCV genotype 1-4. Samatasvir is being evaluated in combination with other direct-acting antiviral agents in subjects with HCV infection.

Bemnifosbuvir (BEM, AT-527), a novel nucleotide analogue inhibitor of the hepatitis C virus NS5B polymerase.

INTRODUCTION: Chronic hepatitis C virus (HCV) persists as a public health concern worldwide. Consequently, optimizing HCV therapy remains an important objective. While current therapies are generally highly effective, advanced antiviral agents are needed to maximize cure rates with potentially shorter treatment durations in a broader patient population, particularly those patients with advanced diseases who remain difficult to treat. AREAS COVERED: This review summarizes the in vitro anti-HCV activity, preclinical pharmacological properties of bemnifosbuvir (BEM, AT-527), a novel prodrug that is metabolically converted to AT-9010, the active guanosine triphosphate analogue that potently and selectively inhibits several viral RNA polymerases, including the HCV NS5B polymerase. Results from clinical proof-of-concept and phase 2 combination studies are also discussed. EXPERT OPINION: BEM exhibits potent pan-genotype activity against HCV, and has favorable safety, and drug interaction profiles. BEM is approximately 10-fold more potent than sofosbuvir against HCV genotypes (GT) tested in vitro. When combined with a potent NS5A inhibitor, BEM is expected to be a promising once-daily oral antiviral for chronic HCV infection of all genotypes and fibrosis stages with potentially short treatment durations.

Profundibacterium mesophilum gen. nov., sp. nov., a novel member in the family Rhodobacteraceae isolated from deep-sea sediment in the Red Sea, Saudi Arabia.

A slow-growing, strictly aerobic, Gram-negative, coccus bacterial strain, designated KAUST100406-0324(T), was isolated from sea-floor sediment collected from the Red Sea, Saudi Arabia. The catalase- and oxidase-positive strain was non-sporulating and only slightly halophilic. Optimum growth occurred at 20-25 °C and at pH values ranging from 7.0 to 8.0. The major cellular fatty acids of the strain were unsaturated C18 : 1ω6c and/or C18 : 1ω7c, C18 : 1ω7c 11-methyl and C16 : 1ω7c and/or C16 : 1ω6c. The major polar lipids were phosphatidylglycerol, phosphatidylethanolamine and two unidentified phospholipids. Ubiquinone 10 was the predominant lipoquinone. The DNA G+C content of strain KAUST100406-0324(T) was 64.0 mol%. Phylogenetic analysis of 16S rRNA gene sequences revealed that the novel strain belonged to the family Rhodobacteraceae of the class Alphaproteobacteria but formed a distinct evolutionary lineage from other bacterial species with validly published names. The 16S rRNA gene sequence of the novel strain was distantly related, but formed a monophyletic cluster with, those of bacteria from two moderately halophilic genera, Hwanghaeicola and Maribius. The similarity of the sequence between the novel strain KAUST100406-0324(T) and the type strains Hwanghaeicola aestuarii Y26(T) (accession number FJ230842), Maribius pelagius B5-6(T) (DQ514326) and Maribius salinus CL-SP27(T) (AY906863) were 94.5 %, 95.2 % and 95.3 %, respectively. Based on the physiological, phylogenetic and chemotaxonomic characteristics presented in this study, we propose that this strain represents a novel species of a new genus in the family Rhodobacteraceae, for which the name of Profundibacterium mesophilum gen. nov., sp. nov. was proposed, with KAUST100406-0324(T) ( = JCM 17872(T)  = NRRL B-59665(T)) as the type strain.

[1,25-(OH)2D3 inhibits lipopolysaccharide-induced expression of interleukin-13 and interleukin-17 in cord blood CD4+T cells].

OBJECTIVE: To study the effect of 1,25-(OH)2D3 on lipopolysaccharide (LPS)-induced expression of interleukin-13 (IL-13) and interleukin-17 (IL-17) in cord blood CD4(+)T cells, providing theoretical basis for clinical reasonable application of vitamin D and prevention of asthma and allergic diseases. METHODS: Mononuclear cells (MNCs) were isolated from umbilical cord blood (50 mL) of 12 normal eutocia term newborns by gravity centrifugation. CD4(+)T cells were isolated using magnetic beads, which was cultured with following three kinds of stimulus for 72 hours: natural state (blank group), LPS (10 µg/mL)stimulation alone and LPS(10 µg/mL)+1,25-(OH)2D3 (10(-8) mmol/L)stimulation. Levels of IL-13 and IL-17 in the culture supernatant and mRNA expressions in cord blood CD4(+)T cells were detected using ELISA and real Time-PCR respectively. RESULTS: Compared with the blank group, levels of IL-13 and IL-17 in the culture supernatant and mRNA expression of IL-13 and IL-17 in the cord blood CD4(+)T cells increased in the LPS stimulation alone group (P<0.01). When co-stimulation of 1,25-(OH)2D3 with LPS, levels of IL-13 and IL-17 in the culture supernatant and mRNA expression of IL-13 and IL-17 in the cord blood CD4(+)T cells decreased compared with LPS-stimulated alone group (P<0.05), but remained higher than the blank group (P<0.01). CONCLUSIONS: LPS can promote expression of IL-13 and IL-17 in cord blood CD4(+)T cells. 1,25-(OH)2D3 inhibits the expression of IL-13 and IL-17, suggesting that vitamin D intake may provide protective effects in the development of atopy-predisposing immune responses in early life.

A Phase 2 Randomized Trial Evaluating the Antiviral Activity and Safety of the Direct-Acting Antiviral Bemnifosbuvir in Ambulatory Patients with Mild or Moderate COVID-19 (MOONSONG Study).

Bemnifosbuvir is an oral antiviral drug with a dual mechanism of action targeting viral RNA polymerase, with in vitro activity against SARS-CoV-2. We conducted a phase 2, double-blind study evaluating the antiviral activity, safety, efficacy, and pharmacokinetics of bemnifosbuvir in ambulatory patients with mild/moderate COVID-19. Patients were randomized 1:1 to bemnifosbuvir 550 mg or placebo (cohort A) and 3:1 to bemnifosbuvir 1,100 mg or placebo (cohort B); all doses were given twice daily for 5 days. The primary endpoint was a change from baseline in the amount of nasopharyngeal SARS-CoV-2 viral RNA by reverse transcription PCR (RT-PCR). The modified intent-to-treat infected population comprised 100 patients (bemnifosbuvir 550 mg, n = 30; bemnifosbuvir 1,100 mg, n = 30; cohort A placebo, n = 30; cohort B placebo, n = 10). The primary endpoint was not met: the difference in viral RNA adjusted means at day 7 was -0.25 log10 copies/mL between bemnifosbuvir 550 mg and cohort A placebo (80% confidence interval [CI], -0.66 to 0.16; P = 0.4260), and -0.08 log10 copies/mL between bemnifosbuvir 1,100 mg and pooled placebo (80% CI, -0.48 to 0.33; P = 0.8083). Bemnifosbuvir 550 mg was well tolerated. Incidence of nausea and vomiting was higher with bemnifosbuvir 1,100 mg (10.0% and 16.7% of patients, respectively) than pooled placebo (2.5% nausea, 2.5% vomiting). In the primary analysis, bemnifosbuvir did not show meaningful antiviral activity on nasopharyngeal viral load as measured by RT-PCR compared with placebo in patients with mild/moderate COVID-19. The trial is registered at ClinicalTrials.gov under registration number NCT04709835. IMPORTANCE COVID-19 continues to be a major global public health challenge, and there remains a need for effective and convenient direct-acting antivirals that can be administered outside health care settings. Bemnifosbuvir is an oral antiviral with a dual mechanism of action and potent in vitro activity against SARS-CoV-2. In this study, we evaluated the antiviral activity, safety, efficacy, and pharmacokinetics of bemnifosbuvir in ambulatory patients with mild/moderate COVID-19. In the primary analysis, bemnifosbuvir did not show meaningful antiviral activity compared with placebo as assessed by nasopharyngeal viral loads. The negative predictive value of nasopharyngeal viral load reduction for clinical outcomes in COVID-19 is currently unclear, and further evaluation of bemnifosbuvir for COVID-19 may be warranted despite the findings observed in this study.

Oral bemnifosbuvir (AT-527) vs placebo in patients with mild-to-moderate COVID-19 in an outpatient setting (MORNINGSKY).

Aim: This phase III study assessed the efficacy/safety/antiviral activity/pharmacokinetics of bemnifosbuvir, a novel, oral nucleotide analog to treat COVID-19. Patients & methods: Outpatient adults/adolescents with mild-to-moderate COVID-19 were randomized 2:1 to bemnifosbuvir/placebo. Time to symptom alleviation/improvement (primary outcome), risk of hospitalization/death, viral load and safety were evaluated. Results: Although the study was discontinued prematurely and did not meet its primary end point, bemnifosbuvir treatment resulted in fewer hospitalizations (71% relative risk reduction), COVID-19-related medically attended hospital visits, and COVID-19-related complications compared with placebo. No reduction in viral load was observed. The proportion of patients with adverse events was similar; no deaths occurred. Conclusion: Bemnifosbuvir showed hospitalization reduction in patients with variable disease progression risk and was well tolerated. Clinical Trial Registration: NCT04889040 (ClinicalTrials.gov).

Safety and efficacy of GSK2248761, a next-generation nonnucleoside reverse transcriptase inhibitor, in treatment-naive HIV-1-infected subjects.

GSK2248761 is a novel, once-daily (QD), next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI) with activity against efavirenz-resistant strains. Two phase I/IIa, double-blind, randomized, placebo-controlled studies investigated the antiviral activity, safety, and pharmacokinetics (PK) of several doses of GSK2248761 monotherapy in treatment-naive HIV-infected subjects. In the initial study, 10 subjects (8 active and 2 placebo) per dose received sequentially descending GSK2248761 monotherapy regimens of 800, 400, 200, and 100 mg QD for 7 days. Because a dose-response relationship was not identified, a second study examined a lower, 30-mg QD dose in 8 subjects (6 active and 2 placebo). Adverse events, viral load (VL), PK, and reverse transcriptase mutations were assessed and combined for analysis. Treatment with GSK2248761 for 7 days was well tolerated with no serious adverse events or discontinuations. The mean VL reductions from baseline on day 8 were 0.97, 1.87, 1.84, 1.81, and 1.78 log(10) copies/ml for GSK2248761 doses of 30, 100, 200, 400, and 800 mg QD, respectively. GSK2248761 PK (maximum drug concentration in serum [C(max)], area under the plasma concentration-time curve from 0 h to the end of the dosing interval [AUC(0-τ)], and concentration at the end of the dosing interval [C(τ)]) increased proportionally over the dose range of 30 to 800 mg QD. The relationship between short-term VL change and GSK2248761 PK was best described by a maximum-effect (E(max)) model using C(τ) (E(max) = 2.0; 50% effective concentration [EC(50)] = 36.9 ng/ml). No NNRTI resistance mutations emerged during the study. GSK2248761 at 100 to 800 mg QD for 7 days was well tolerated, demonstrated potent antiviral activity in treatment-naive HIV-infected subjects, and had favorable PK and resistance profiles. GSK2248761 is no longer in clinical development.

Short-term monotherapy with IDX184, a liver-targeted nucleotide polymerase inhibitor, in patients with chronic hepatitis C virus infection.

IDX184 is a liver-targeted prodrug of 2'-methylguanosine (2'-MeG) monophosphate. This study investigated the safety, tolerability, antiviral activity, and pharmacokinetics of IDX184 as a single agent in treatment-naïve patients with genotype-1 chronic hepatitis C virus (HCV) infection. Forty-one patients with baseline HCV RNA ≥ 5 log(10) IU/ml, alanine aminotransferase (ALT) ≤ 2.5× the upper limit of normal, and compensated liver disease were dosed. Sequential cohorts of 10 patients, randomized 8:2 (active:placebo), received 25, 50, 75, and 100 mg of IDX184 once daily for 3 days, with a 14-day follow-up. There were no safety-related treatment discontinuations or serious adverse events. The adverse events and laboratory abnormalities observed for IDX184- and placebo-treated patients were similar. At the end of the 3-day treatment period, changes from baseline in HCV RNA levels (means ± standard deviations) were -0.5 ± 0.6, -0.7 ± 0.2, -0.6 ± 0.3, and -0.7 ± 0.5 log(10) for the 25-, 50-, 75-, and 100-mg doses, respectively, while viral load remained unchanged for the pooled placebo patients (-0.05 ± 0.3 log(10)). Patients with genotype-1a and patients with genotype-1b responded similarly. Serum ALT levels decreased, especially at daily doses ≥ 75 mg. During the posttreatment period, plasma viremia and serum aminotransferase levels returned to near pretreatment levels. No resistance mutations associated with IDX184 were detected. Plasma exposure of IDX184 and its nucleoside metabolite 2'-MeG was dose related and low. Changes in plasma viral load correlated with plasma exposure of 2'-MeG. In conclusion, the results from this proof-of-concept study show that small doses of the liver-targeted prodrug IDX184 were able to deliver significant antiviral activity and support further clinical evaluation of the drug candidate.

Marinobacter xestospongiae sp. nov., isolated from the marine sponge Xestospongia testudinaria collected from the Red Sea.

A Gram-negative, catalase- and oxidase-positive, non-sporulating, rod-shaped and slightly halophilic bacterial strain, designated UST090418-1611(T), was isolated from the marine sponge Xestospongia testudinaria collected from the Red Sea coast of Saudi Arabia. Phylogenetic trees based on the 16S rRNA gene sequence placed strain UST090418-1611(T) in the family Alteromonadaceae with the closest relationship to the genus Marinobacter. The 16S rRNA gene sequence similarity between the strain and the type strains of recognized Marinobacter species ranged from 92.9 to 98.3%. Although strain UST090418-1611(T) shared high 16S rRNA gene sequence similarity with Marinobacter mobilis CN46(T), M. zhejiangensis CN74(T) and M. sediminum R65(T) (98.3, 97.4 and 97.3%, respectively), the relatedness of the strain to these three strains in DNA-DNA hybridization was only 58, 56 and 33%, respectively, supporting the novelty of the strain. In contrast to most strains in the genus Marinobacter, strain UST090418-1611(T) tolerated only 6% (w/v) NaCl, and optimal growth occurred at 2.0% (w/v) NaCl, pH 7.0-8.0 and 28-36 °C. The predominant cellular fatty acids were C(12:0) 3-OH, C(16:0), C(12:0) and summed feature 3 (C(16:1)ω6c and/or C(16:1)ω7c). The genomic DNA G+C content was 57.1 mol%. Based on the physiological, phylogenetic and chemotaxonomic characteristics presented in this study, we suggest that the strain represents a novel species in the genus Marinobacter, for which the name Marinobacter xestospongiae sp. nov. is proposed, with UST090418-1611(T) ( = JCM 17469(T)  = NRRL B-59512(T)) as the type strain.

Erythrobacter pelagi sp. nov., a member of the family Erythrobacteraceae isolated from the Red Sea.

A novel Gram-negative, aerobic, catalase- and oxidase-positive, non-sporulating, non-motile, rod-shaped bacterium, designated strain UST081027-248(T), was isolated from seawater of the Red Sea. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain UST081027-248(T) fell within the genus Erythrobacter. Levels of 16S rRNA gene sequence similarity between the novel strain and the type strains of Erythrobacter species ranged from 95.3 % (with Erythrobacter gangjinensis) to 98.2 % (with Erythrobacter citreus). However, levels of DNA-DNA relatedness between strain UST081027-248(T) and the type strains of closely related species were below 70 %. Optimal growth of the isolate occurred in the presence of 2.0 % NaCl, at pH 8.0-9.0 and at 28-36 °C. The isolate did not produce bacteriochlorophyll a. The predominant cellular fatty acids were C(17:1)ω6c, summed feature 8 (C(18:1)ω6c and/or C(18:1)ω7c) and C(15:0) 2-OH. The genomic DNA G+C content of strain UST081027-248(T) was 60.4 mol%. Phenotypic properties and phylogenetic distinctiveness clearly indicated that strain UST081027-248(T) represents a novel species of the genus Erythrobacter, for which the name Erythrobacter pelagi sp. nov. is proposed. The type strain is UST081027-248(T) ( = JCM 17468(T) = NRRL 59511(T)).

Drug interaction profile for GSK2248761, a next generation non-nucleoside reverse transcriptase inhibitor.

AIM: To evaluate potential drug interactions with antiretroviral therapies or supportive therapies for use in conjunction with the once daily, next generation non-nucleoside reverse transcriptase inhibitor GSK2248761 in patients with HIV-1 infection. METHODS: A series of phase I drug interaction studies was conducted. RESULTS: GSK2248761 was shown to be a weak CYP3A4 and CYP2D6 inhibitor in a clinical study with a probe cocktail. Mean plasma concentration-time profiles for atazanavir, tenofovir disoproxil fumarate/emtricitabine (TDF/FTC), darunavir (DRV, administered with ritonavir [RTV]), and drospirenone/ethinylestradiol were similar following co-administration of GSK2248761. Plasma raltegravir AUC(0,τ) and C(max) increased by 18% with no change in Cτ when raltegravir was co-administered with GSK2248761. Lopinavir (LPV) plasma AUC(0,τ), C(max) and Cτ decreased by 23%, 14% and 40%, respectively, following administration of lopinavir/ritonavir with GSK2248761. Atorvastatin, rosuvastatin and simvastatin AUC(0,∞) and C(max) increased following co-administration with GSK2248761, with the largest changes observed for simvastatin (3.7-fold and 4.3-fold). Changes in maximum and extent of GSK2248761 exposure were marginal after co-administration with atazanavir, TDF/FTC and raltegravir compared with GSK2248761 administered alone. Co-administration of GSK2248761 with DRV/RTV and LPV/RTV increased plasma GSK2248761 exposures by 1.25- to ≤2-fold compared with GSK2248761 administered alone, and increases in GSK2248761 exposure were higher following single dose co-administration of DRV/RTV or LPV/RTV compared with multiple doses. There were few drug-related AEs, and no treatment-related trends in blood chemistry, haematology, urinalysis, vital signs or ECG findings. CONCLUSIONS: These studies indicate that GSK2248761 was safe and well tolerated in healthy adults treated in these studies at the doses and duration of therapy evaluated.