Chemoreactive-Inspired Discovery of Influenza A Virus Dual Inhibitor to Block Hemagglutinin-Mediated Adsorption and Membrane Fusion

Journal of Medicinal Chemistry
Guangwei WuDehai Li

Abstract

Owing to the emergence of drug resistance and high morbidity and mortality, the need for novel anti-influenza A virus (IAV) drugs with divergent targets is highly sought after. Herein, we reveal the discovery of an anti-IAV agent as a dual inhibitor to block hemagglutinin-mediated adsorption and membrane fusion using a chemoreactive ortho-quinone methide (o-QM) equivalent. Based on the o-QM equivalent nonenzymatically multipotent behavior, we created a series of clavatol-derived pseudo-natural products and found that penindolone (PND), a new diclavatol indole adduct, exhibited potent and broad-spectrum anti-IAV activities with low risk of inducing drug resistance. Distinct from current anti-IAV drugs, PND possesses a novel scaffold and is the first IAV inhibitor targeting both HA1 and HA2 subunits of virus hemagglutinin to dually block the IAV adsorption and membrane fusion process. More importantly, intranasal and oral administration of PND can protect mice against IAV-induced death and weight loss, superior to the effects of the clinical drug oseltamivir. Thus, the use of chemoreactive intermediates could expand our understanding of chemical diversity and aid in the development of anti-IAV drugs with novel targets.

References

Jul 1, 1992·Antimicrobial Agents and Chemotherapy·M HosoyaS Shigeta
Apr 9, 2004·Journal of the American Chemical Society·Uwe RixJürgen Rohr
Dec 2, 2006·Nature Reviews. Drug Discovery·Erik De Clercq
Dec 14, 2006·The Journal of Infectious Diseases·Frederick G Hayden, Andrew T Pavia
May 1, 2008·Euro Surveillance : Bulletin Européen Sur Les Maladies Transmissibles = European Communicable Disease Bulletin·A LackenbyM C Zambon
Nov 14, 2008·Proceedings of the National Academy of Sciences of the United States of America·Rupert J RussellJohn J Skehel
Jun 16, 2009·Nature·Gabriele NeumannYoshihiro Kawaoka
Sep 29, 2009·European Journal of Cardio-thoracic Surgery : Official Journal of the European Association for Cardio-thoracic Surgery·Sotiris C StamouKevin W Lobdell
Dec 24, 2010·PloS One·Andreas LeibbrandtAndreas Grassauer
Oct 18, 2011·The Journal of Organic Chemistry·Tejas P Pathak, Matthew S Sigman
Jun 29, 2012·Journal of Virology·Evelien VanderlindenLieve Naesens
Jul 11, 2013·Organic Letters·Justin T J Spence, Jonathan H George
Sep 17, 2014·The Journal of Antimicrobial Chemotherapy·S HussainJ W McCauley
Feb 15, 2015·European Journal of Medicinal Chemistry·Xueqing ChenWenhan Lin
Nov 18, 2015·Journal of Chemical Theory and Computation·James A MaierCarlos Simmerling
Nov 19, 2015·Acta Pharmaceutica Sinica. B·Zuyuan ShenWei Wang
Feb 9, 2016·Journal of Natural Products·David J Newman, Gordon M Cragg
Dec 23, 2016·Proceedings of the National Academy of Sciences of the United States of America·Rameshwar U Kadam, Ian A Wilson
Jun 12, 2017·Journal of Molecular Graphics & Modelling·Ming-Jing LiRi-Lei Yu
Oct 4, 2017·Science·Rameshwar U KadamIan A Wilson
Mar 9, 2019·Science·Maria J P van DongenIan A Wilson

❮ Previous
Next ❯

Citations

Mar 2, 2021·Angewandte Chemie·George KarageorgisHerbert Waldmann
Apr 23, 2021·Scientific Reports·Yu-Jen ChangChih-Hao Lu
Oct 21, 2021·Journal of Chemical Information and Modeling·José-Manuel GallyHerbert Waldmann
Feb 3, 2022·Journal of Natural Products·Trevor N PurdyApril L Lukowski

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.