Macrocyclic mechanism-based inhibitor for neuraminidases
Hirokazu Kai1, Hiroshi Hinou, Kentaro Naruchi
1Graduate School of Life Science and Faculty of Advanced Life Science, Hokkaido University, N21, W11, Sapporo 001-0021, Japan.
Chemistry (Weinheim an Der Bergstrasse, Germany)
|December 13, 2012
Summary
A novel macrocyclic inhibitor irreversibly blocks neuraminidases (NAs) by maintaining its structure in the active site. This irreversible inhibition is effective against NAs with low catalytic rates, offering a new strategy for NA-targeted therapies.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Enzyme Inhibition
Background:
- Neuraminidases (NAs) are crucial enzymes in various biological processes.
- Developing effective NA inhibitors is important for therapeutic applications.
- Existing inhibitors may lose efficacy under certain conditions, like detergent presence.
Purpose of the Study:
- To synthesize and evaluate a novel macrocyclic mechanism-based inhibitor for neuraminidases.
- To investigate the structural requirements for irreversible NA inhibition.
- To determine the relationship between inhibitor efficacy and NA catalytic activity (kcat).
Main Methods:
- Synthesis of a macrocyclic inhibitor with a 2-difluoromethylphenyl aglycone and sialic acid.
- Evaluation of inhibitory activity against various neuraminidases, including Vibrio cholerae NA (VCNA).
- Assessing inhibitor performance in the presence of detergent to mimic physiological conditions.
Main Results:
- The macrocyclic inhibitor demonstrated irreversible inhibition of VCNA, even with detergent present.
- Irreversible inhibition was observed for NAs with low kcat values (e.g., Influenza, Human NAs).
- Salmonella typhimurium NA, with a high kcat, was not irreversibly inhibited.
Conclusions:
- The macrocyclic structure is key to maintaining inhibitor presence in the NA active site post-cleavage.
- Irreversible inhibition by this compound is inversely related to the target NA's kcat.
- This inhibitor offers a unique mechanism for targeting specific NAs, distinct from conventional kcat inhibitors.
Related Concept Videos
01:29Indirect-Acting Cholinergic Agonists: Chemistry and Structure-Activity Relationship
Indirect-acting cholinergic agonists are agents that interact with the acetylcholinesterase enzyme in the synaptic cleft, preventing the breakdown of acetylcholine into choline and acetate. Consequently, the concentration of acetylcholine in the synaptic cleft increases. These agonists can be classified into reversible and irreversible inhibitors based on their duration of action.
Reversible inhibitors display short to medium durations of action. Short-acting agents include simple alcohols with...
Reversible inhibitors display short to medium durations of action. Short-acting agents include simple alcohols with...
01:18Indirect-Acting Cholinergic Agonists: Mechanism of Action
Indirect-acting cholinergic agonists work by interacting with an enzyme called acetylcholinesterase (AChE) in the synaptic cleft. They can be reversible or irreversible inhibitors and have different effects on the enzyme.
Reversible inhibitors like edrophonium bind to a specific part of the enzyme called the anionic catalytic site. They form noncovalent bonds, which means they are not strongly attached to the enzyme. This creates a temporary and less stable enzyme–inhibitor complex, leading to...
Reversible inhibitors like edrophonium bind to a specific part of the enzyme called the anionic catalytic site. They form noncovalent bonds, which means they are not strongly attached to the enzyme. This creates a temporary and less stable enzyme–inhibitor complex, leading to...
01:30Inhibitors of Viral Protein Synthesis
Protein synthesis is indispensable for viral replication, as viruses lack the cellular machinery required for this process and must hijack the host's translational apparatus. In response, host cells deploy a critical innate immune defense involving interferons, specialized cytokines that play a central role in inhibiting viral propagation.Upon viral detection, infected cells release interferons that bind to receptors on adjacent uninfected cells, activating the JAK-STAT signaling pathway and...
01:27Influenza
Influenza is an acute, highly communicable viral disease that affects the respiratory tract and is responsible for seasonal epidemics worldwide. Influenza A is the most prevalent type associated with widespread outbreaks and is subtyped based on two surface glycoproteins: hemagglutinin (H) and neuraminidase (N), as in H1N1. These glycoproteins are essential for viral infectivity, transmission, and immune recognition. Transmission occurs primarily through respiratory droplets and contaminated...
01:17Nondepolarizing (Competitive) Neuromuscular Blockers: Mechanism of Action
Nondepolarizing neuromuscular blockers induce paralysis by competitively blocking nicotinic acetylcholine receptors at the muscle end plate. Examples include pancuronium, mivacurium, vecuronium, and rocuronium. These quaternary ammonium derivatives are administered intravenously, are poorly absorbed, and are excreted via the kidneys.
Competitive antagonists prevent acetylcholine from binding to its receptor, inhibiting membrane depolarization. Without conformational changes or intrinsic...
Competitive antagonists prevent acetylcholine from binding to its receptor, inhibiting membrane depolarization. Without conformational changes or intrinsic...
01:15Anthelminthic Agents
Anthelmintic drugs differ significantly from antiparasitic therapies targeting protozoa, primarily due to differences in parasite biology. Whereas most protozoal treatments act on proliferating cells, anthelmintics are typically directed against mature, nonproliferative helminths. The therapeutic approach considers the helminth's reliance on neuromuscular coordination, glucose metabolism, and microtubular integrity for survival, reproduction, and localization within the host. Most anthelmintics...