Influenza outbreaks cause pandemics in millions of people. The treatment of influenza remains a challenge due to significant genetic polymorphism in the influenza virus. Also, developing vaccines to protect against seasonal and pandemic influenza infections is constantly impeded. Thus, antibiotics are the only first line of defense against antigenically distinct strains or new subtypes of influenza viruses. Among several anti-influenza targets, the M2 protein of the influenza virus performs several activities. M2 protein is an ion channel that permits proton conductance through the virion envelope and the deacidification of the Golgi apparatus. Both these functions are critical for viral replication. Thus, targeting the M2 protein of the influenza virus is an essential target. Rimantadine and amantadine are two well-known drugs that act on the M2 protein. However, these drugs acquired resistance to influenza and thus are not recommended to treat influenza infections. This review discusses an overview of anti-influenza therapy, M2 ion channel functions, and its working principle. It also discusses the M2 structure and its role, and the change in the structure leads to mutant variants of influenza A virus. We also shed light on the recently identified compounds acting against wild-type and mutated M2 proteins of influenza virus A. These scaffolds could be an alternative to M2 inhibitors and be developed as antibiotics for treating influenza infections.

01 Feb 2024·Expert Opinion on Therapeutic Targets

Kv1.3 in the spotlight for treating immune diseases

Review

Author: Colomer-Molera, Magalí ; Capera, Jesusa ; Cassinelli, Silvia ; Navarro-Pérez, María ; Benavente-Garcia, Anna ; Felipe, Antonio

INTRODUCTIONKv1.3 is the main voltage-gated potassium channel of leukocytes from both the innate and adaptive immune systems. Channel function is required for common processes such as Ca²⁺ signaling but also for cell-specific events. In this context, alterations in Kv1.3 are associated with multiple immune disorders. Excessive channel activity correlates with numerous autoimmune diseases, while reduced currents result in increased cancer prevalence and immunodeficiencies.AREAS COVEREDThis review offers a general view of the role of Kv1.3 in every type of leukocyte. Moreover, diseases stemming from dysregulations of the channel are detailed, as well as current advances in their therapeutic research.EXPERT OPINIONKv1.3 arises as a potential immune target in a variety of diseases. Several lines of research focused on channel modulation have yielded positive results. However, among the great variety of specific channel blockers, only one has reached clinical trials. Future investigations should focus on developing simpler administration routes for channel inhibitors to facilitate their entrance into clinical trials. Prospective Kv1.3-based treatments will ensure powerful therapies while minimizing undesired side effects.

01 Sep 2023·European Journal of Medicinal Chemistry

Development of isoselenazolium chlorides as selective pyruvate kinase isoform M2 inhibitors

Article

Author: Pantelejevs, Teodors ; Dimitrijevs, Pavels ; Hyvönen, Marko ; Makrecka-Kuka, Marina ; Bogucka, Agnieszka ; Arsenyan, Pavel

Alterations in cancer metabolic pathways open up an opportunity for targeted and effective elimination of tumor cells. Pyruvate kinase M2 (PKM2) is predominantly expressed in proliferating cells and plays an essential role in directing glucose metabolism in cancer. Here, we report the design of novel class of selective PKM2 inhibitors as anti-cancer agents and their mechanism of action. Compound 5c being the most active with IC₅₀ = 0.35 ± 0.07 μM, also downregulates PKM2 mRNA expression, modulates mitochondrial functionality, induces oxidative burst and is cytotoxic for various cancer types. Isoselenazolium chlorides have an unusual mechanism of PKM2 inhibition, inducing a functionally deficient tetrameric assembly, while exhibiting a competitive inhibitor character. The discovery of robust PKM2 inhibitors not only offers candidates for anticancer therapy but is also crucial for studying the role of PKM2 in cancer.

100 Deals associated with M2 proton channel inhibitors(Ambrilia Biopharma, Inc.)

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Indication	Highest Phase	Country/Location	Organization	Date
Influenza A virus infection	Preclinical	-	Ambrilia Biopharma, Inc.	-

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M2 proton channel inhibitors(Ambrilia Biopharma, Inc.)

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