Preparation of eicosavalent triazolylsialoside-conjugated human serum albumin as a dual hemagglutinin/neuraminidase inhibitor and virion adsorbent for the prevention of influenza infection.
作者: Yang Li ; Han-Yu Liu ; Ming-Jiang Yang ; Dong Liu ; Jia-Qi Song ; Zhiqi Lao ; Yue Chen ; Yang Yang
A triazolylsialoside-human serum albumin conjugate was prepared as a multivalent hemagglutinin and neuraminidase inhibitor using a di-(N-succinimidyl) adipate strategy. Matrix-Assisted Laser Desorption/Ionization-Time of Flight-Mass Spectrometry (MALDI-TOF-MS) indicated that five tetravalent sialyl galactosides were grafted onto the protein backbone resulting in an eicosavalent triazolylsialoside-protein complex. Compared with monomeric sialic acid, molecular interaction studies showed that the synthetic pseudo-glycoprotein bound tightly not only to hemagglutinin (HA)/neuraminidase (NA) but also to mutated drug-resistant NA on the surface of the influenza virus with a dissociation constant (KD) in the 1 μM range, attributed to the cluster effect. Moreover, this glycoconjugate exhibited potent antiviral activity against a broad spectrum of virus strains and showed no cytotoxicity towards Human Umbilical Vein Endothelial Cells (HUVECs) and Madin-Darby canine kidney (MDCK) cells at high concentrations. Further mechanistic studies demonstrated this multivalent sialyl conjugate showed strong capture and trapping of influenza virions, thus disrupting the ability of the influenza virus to infect host cells. This research lays the experimental foundation for the development of new antiviral agents based on multivalent sialic acid-protein conjugates.
2023-08-21·BMC infectious diseases
Clinical characteristics of severe influenza virus-associated pneumonia complicated with bacterial infection in children: a retrospective analysis.
作者: Qiong-Yu Wang ; Lin Yuan ; Jia-Yi Lin ; Zhi-Qiang Zhuo ; Yong-Mei Wang ; Si-Si Li ; Min Zhang ; Xing-Dong Wu
We aimed to investigate the clinical characteristics of severe influenza virus-associated pneumonia complicated with bacterial infection in children.
We retrospectively analysed data concerning 64 paediatric patients with severe influenza virus-associated pneumonia who had been treated at our hospital. The patients were divided into observation (44 patients) and control (20 patients) groups, based on the presence or absence of concomitant bacterial infection, and clinical data were compared between the groups.
The mean age in the observation group was 2.71 ± 1.44 years, 42 (95.45%) were aged ≤ 5 years, and 18 (40.9%) had underlying diseases. The mean age in the control group was 4.05 ± 2.21 years, 13 (65%) were aged ≤ 5 years, and 3 (15%) had underlying diseases. There was a statistically significant difference in patient age and the proportion of patients with underlying diseases (P < 0.05). The observation group had higher duration of fever values, a higher number of patients with duration of fever ≥ 7 days, a higher incidence of gasping, and a higher incidence of seizures/consciousness disturbance, and the differences were statistically significant (P < 0.05). Secondary bacterial infections in the observation group were mainly due to gram-negative bacteria, with Haemophilus influenzae and Moraxella catarrhalis being the most common pathogens. The observation group had a higher proportion of patients treated in the paediatric intensive care unit and a longer hospital stay, and the differences were statistically significant (P < 0.05).
Severe influenza virus-associated pneumonia complicated with bacterial infection was more common in children aged ≤ 5 years. Younger patients with underlying diseases were more susceptible to bacterial infection (mainly due to gram-negative bacteria). The timely administration of neuraminidase inhibitors and antibiotics against susceptible bacteria is likely to help improve cure rates.
Resistance profiles for the investigational neuraminidase inhibitor AV5080 in influenza a and B viruses.
作者: Andrei A Ivashchenko ; Jeremy C Jones ; Dmitry O Shkil ; Yan A Ivanenkov ; Philippe Noriel Q Pascua ; Melissa Penaflor ; Ruben N Karapetian ; Elena A Govorkova ; Alexandre V Ivachtchenko
Neuraminidase inhibitors (NAIs) are recommended for influenza treatment and prevention worldwide. The most widely prescribed NAI is oral oseltamivir, while inhaled zanamivir is less commonly used. Using phenotypic neuraminidase (NA) enzymatic assays and molecular modeling approaches, we examined the ability of the investigational orally-dosed NAI AV5080 to inhibit viruses of the influenza A (H1N1)pdm09, A (H3N2), A (H5N1), and A (H7N9) subtypes and the influenza B/Victoria- and B/Yamagata-lineages containing NA substitutions conferring oseltamivir or zanamivir resistance including: NA-R292K, NA-E119 G/V, NA-H274Y, NA-I122 L/N, and NA-R150K. Broadly, AV5080 showed enhanced in vitro efficacy when compared with oseltamivir and/or zanamivir. Reduced AV5080 inhibition was determined for influenza A viruses with NA-E119G and NA-R292K, and for B/Victoria-lineage viruses with NA-I122 N/L and B/Yamagata-lineage virus with NA-R150K. Molecular modeling suggested loss of the short hydrogen bond to the carboxyl group of AV5080 affected inhibition of NA-R292K viruses, whereas loss of the salt bridge with the guanidine group of AV5080 affected inhibition of NA-E119G. The resistance profiles and predicted binding modes of AV5080 and zanamivir are most similar, but dissimilar to those of oseltamivir, in part because of a guanidine moiety compensatory binding effect. Overall, our data suggests that AV5080 is a promising oral-dosed NAI that exhibited similar or superior in vitro efficacy against viruses with reduced or highly reduced inhibition phenotypes with respect to currently approved NAIs.
Japanese researchers analyze the impact of geographical differences and income on seasonal influenza-related deaths between 2001 and 2018
OKAYAMA, Japan, Sept. 1, 2023 /PRNewswire/ --
Influenza, a major respiratory infection, is responsible for many deaths across the globe, annually. Researchers from Japan have now used WHO mortality data to analyze trends in influenza-associated mortality. Their findings revealed that death rates are consistently rising since 2009 with variations influenced by geography and income levels. This study data serves as a benchmark for public health providers and policymakers to combat influenza-associated mortality.
There has been a concerning increasein global mortality rates since 2009 due to influenza, underscoring the urgent need for effective international influenza control strategies.
Influenza is a leading cause of respiratory diseases, contributing to a significant number of deaths worldwide. To understand the current impact of influenza on global health, a research team led by Professor Hideharu Hagiya and Professor Toshihiro Koyama of Okayama University, Japan, analyzed the trends in seasonal influenza-associated mortality using data from the World Health Organization (WHO) mortality database. Their findings were made available online on June 16, 2023, in the Journal of Infection.
First, the team acquired detailed death count data caused by seasonal influenza in 65 countries, between 2001 and 2018. "We assessed influenza-associated mortality using two parameters: crude mortality rate (CR) and age-standardized mortality rates, considering age structure variations among populations. The analysis, utilizing locally estimated scatterplot smoothing curve, offered insights into global and long-term patterns," explains Prof. Koyama.
The study revealed a concerning 4.8-fold increase in influenza-associated mortality from 2009 to 2018. Geographically, all five regions, selected based on WHO country groupings, exhibited a rising trend in mortality rates, with Western Europe, North America, and the Western Pacific experiencing faster increases. Age-wise, influenza CR increased in all regions, but a decline was observed among the older population in Eastern Europe and Central and South America.
Income-level analyses revealed that the high-income group demonstrated an upward trajectory from 2009 onwards, while the upper-middle income group maintained a stable rate with recent increases. In contrast, the lower-middle and low-income groups showed steady or decreasing mortality rates.
Despite a decline in mortality rates from 2001 to 2009, the global trend reversed and continued to increase after 2009. This can be attributed to factors such as genetic drift, herd immunity, early treatment due to rapid diagnostic tests, and the development of neuraminidase inhibitors. Discussing the future implications, Prof. Koyama muses, "Our findings can increase the international attention to influenza, encouraging more countries to focus on influenza surveillance and prevention, eventually enhancing global health. We also hope that researchers who wish to use international health databases to improve global health find this study useful."
Title of original paper: Global trends of seasonal influenza-associated mortality in 2001–2018: A longitudinal epidemiological study
Journal: Journal of Infection
SOURCE Okayama University
SAN DIEGO, May 03, 2023 (GLOBE NEWSWIRE) -- Cidara Therapeutics Inc. (Nasdaq: CDTX), a biotechnology company developing long-acting therapeutics designed to save lives and improve the standard of care for patients facing serious diseases, is delivering two oral presentations highlighting new preclinical data on its novel drug-Fc conjugate (DFC) candidate targeting influenza A and B, CD388, at the 7th International Society for Influenza and Other Respiratory Virus Diseases (ISIRV) conference in Seattle, Washington, May 3-5, 2023.
“These encouraging CD388 preclinical data provide further support for the potential of our Cloudbreak® DFC programs,” said Jeffrey Stein, Ph.D., president and chief executive officer of Cidara. “CD388 has shown potential activity against seasonal and pandemic influenza strains, as well as activity against influenza strains resistant to neuraminidase inhibitors, the current standard of care. We look forward to building on these promising data for the clinical advancement of CD388 and continuing to leverage our Cloudbreak platform to help develop targeted therapeutics designed to inhibit specific disease targets, including in influenza and cancer.”
Presentation details and key highlights for the two oral presentations can be found below.
Oral presentation details:
Title: CD388, a Novel Drug Fc-Conjugate (DFC), Demonstrates Potent, Universal Activity Against Influenza A and B
Session: Preclinical Development
Presenter: James Levin, Ph.D., Senior Director of Preclinical Development at Cidara
Date and Time: May 3, 2023, at 2:30 – 2:45 p.m. PT
CD388 has broad spectrum activity against seasonal and pandemic influenza A and B strains in vitro, including highly pathogenic and neuraminidase-resistant isolates.
The in vitro potency of CD388 translated into a high level of protection in mouse survival and quantitative lung burden treatment models.
Title: CD388 Demonstrates a High Barrier to Resistance and Retains Potent Activity Against NAIR Influenza A and B Variants
Session: Antivirals, Monoclonal Antibodies and Combinations
Presenter: Simon Doehrmann, Ph.D, Senior Scientist at Cidara
Date and Time: May 4, 2023, at 11:35 - 11:50 a.m. PT
CD388 retained potency against neuraminidase inhibitor-resistant variants and demonstrated a high barrier of resistance development in vitro. No CD388 specific resistance mechanisms were identified.
Cidara is currently advancing its Cloudbreak DFC program in an ongoing Phase 2a trial being conducted in collaboration with Janssen Pharmaceuticals, Inc (Janssen), one of the Janssen Pharmaceutical Companies of Johnson & Johnson that is evaluating the pre-exposure prophylactic activity of CD388 against the H3N2 influenza A virus strain. The Company recently announced promising interim efficacy and safety data from the Phase 2a study. Cidara is additionally advancing its first oncology DFC candidate, CD421, a first-in-class inhibitor of CD73, with an IND anticipated in 2024.
About Cidara Therapeutics
Cidara is developing long-acting therapeutics designed to improve the standard of care for patients facing serious diseases. The company’s portfolio comprises new approaches aimed at transforming existing treatment and prevention paradigms, including drug-Fc conjugates (DFCs) from its proprietary Cloudbreak® platform targeting oncologic and viral diseases. In addition, Cidara recently received FDA approval for REZZAYO™ (rezafungin for injection), which it has licensed to multiple partners to commercialize in the U.S. and ex-U.S. Cidara is headquartered in San Diego, California. For more information, please visit .
This release contains “forward-looking statements” within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, and such forward-looking statements are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. “Forward-looking statements” describe future expectations, plans, results, or strategies and are generally preceded by words such as “anticipates,” “believe,” “could,” “expect,” “may,” “plan” or “will”. Forward-looking statements in this release include, but are not limited to, statements related to whether the nonclinical data generated for CD388 will be predictive of therapeutic activity in humans, whether any Cloudbreak DFC candidate will be safe or effective, and whether we will submit an IND for CD421 in 2024r. Such statements are subject to a multitude of risks and uncertainties that could cause future circumstances, events, or results to differ materially from those projected in the forward-looking statements, such as unanticipated delays in or negative results from Cidara’s preclinical or clinical trials, delays in action by regulatory authorities due to limitations on inspections and other COVID-19-related effects, and impacts of the COVID-19 pandemic or other obstacles on the enrollment of patients or other aspects of CD388 development. These and other risks are identified under the caption “Risk Factors” in Cidara’s Annual Report on Form 10-K for the fiscal year ended December 31, 2022 and other filings subsequently made with the Securities and Exchange Commission. All forward-looking statements contained in this press release speak only as of the date on which they were made and are based on management’s assumptions and estimates as of such date. Cidara does not undertake any obligation to publicly update any forward-looking statements, whether as a result of the receipt of new information, the occurrence of future events or otherwise.