Small molecule covalent inhibitors, or called as irreversible inhibitors, are a type of inhibitors that exert their biological functions by irreversibly binding to target through covalent bonds. Compared with non-covalent inhibitors, covalent inhibitors have obvious advantages in bioactivity. Nevertheless, these agents may also exhibit larger toxicity once off-target effects arise. This "double-edged swords" property often leads drug researchers to avoid attaching them. In recent years, some problems such as drug resistance are difficult to be solved with reversible inhibitors leading researchers to pay more attention on the covalent inhibitors. In this review, we shall make a short summary to the recent research progress of covalent inhibitors and the interaction modes between covalent inhibitors and their target protein residues.
Amino Acids ; chemistry ; Antineoplastic Agents ; chemical synthesis ; chemistry ; therapeutic use ; Antiviral Agents ; chemical synthesis ; chemistry ; therapeutic use ; Drug Discovery ; Drug Resistance ; Enzyme Inhibitors ; chemical synthesis ; chemistry ; therapeutic use ; Hepatitis C ; drug therapy ; Humans ; Molecular Structure ; Neoplasms ; drug therapy ; Protein Binding ; Protein Kinase Inhibitors ; chemical synthesis ; chemistry ; therapeutic use ; Receptor, Epidermal Growth Factor ; antagonists & inhibitors ; Serine Proteinase Inhibitors ; chemical synthesis ; chemistry ; therapeutic use

We have previously shown that cycloheximide significantly inhibited apoptosis, and reduced ensuing cerebral infarction in a newborn rat model of cerebral hypoxiaischemia. This study was performed to determine the therapeutic window for cycloheximide therapy. Seven day-old newborn rat pups were subjected to 100 min of 8% oxygen following a unilateral carotid artery ligation, and cycloheximide was given at 0, 6, 12 and 24 hr after hypoxia-ischemia (HI). Apoptosis or necrosis was identified by performing flow cytometry with a combination of fluorescinated annexin V and propidium iodide, and the extent of cerebral infarction was evaluated with triphenyl tetrazolium chloride (TTC) at 48 hr and 72 hr after HI, respectively. With cycloheximide treatment at 0 hr after HI, both apoptotic and necrotic cells by flow cytometry were significantly reduced, only necrotic cells were significantly reduced at 6 and 12 hr, and no protective effect was seen if administration was delayed until 24 hr after HI compared to the HI control group. Infarct volume, measured by TTC, was significantly reduced by 92% and 61% when cycloheximide was given at 0 or 6 hr after HI respectively; however, there was an insignificant trend in infarct reduction if cycloheximide was administered 12 hr after HI, and no protective effect was observed when administration was delayed until 24 hr after HI. In summary, cycloheximide was neuroprotective when given within 6 hr after HI in the developing newborn rat brain.
Rats, Sprague-Dawley ; Rats ; Protein Synthesis Inhibitors/therapeutic use ; Oxygen/metabolism ; Neuroprotective Agents/*therapeutic use ; Necrosis ; Hypoxia-Ischemia, Brain/*drug therapy ; Hypoxia, Brain ; Humans ; Flow Cytometry ; Cycloheximide/*therapeutic use ; Brain Ischemia ; Apoptosis ; Animals, Newborn ; Animals

Alzheimer's disease (AD) is a complex neurodegenerative disorder which seriously causes the dementia in elderly people and afflicts millions of people worldwide. Drug discovery for Alzheimer's disease therapy has been a hot research area and a big challenge, in which development of acetylcholinesterase (AChE) inhibitors design was the most active and some AChE inhibitors are commercially available for AD medication already. However, practical using of commercial AChE inhibitors showed their limited usefulness and related adverse effects. Thus, it is extremely urgent to find novel AChE inhibitors with higher potency and less adverse effects. Based on the accurate crystallographic studies about AChE, strategies for multi-binding site AChE inhibitors have been formed, followed by design of the multi-target directed ligands. In this review, the structures and binding modes of commercial AChE inhibitors were briefly discussed, together with the development of AChE inhibitor design for AD therapy: from multi-binding site inhibitors to multi-target directed ligands.
Acetylcholinesterase ; chemistry ; metabolism ; Alzheimer Disease ; drug therapy ; Amyloid Precursor Protein Secretases ; antagonists & inhibitors ; Amyloid beta-Peptides ; metabolism ; Animals ; Aspartic Acid Endopeptidases ; antagonists & inhibitors ; Binding Sites ; Butyrylcholinesterase ; chemistry ; metabolism ; Cholinesterase Inhibitors ; chemical synthesis ; chemistry ; pharmacology ; therapeutic use ; Drug Design ; Humans ; Ligands ; Monoamine Oxidase Inhibitors ; chemical synthesis ; chemistry ; Receptors, N-Methyl-D-Aspartate ; antagonists & inhibitors ; Structure-Activity Relationship

A series of aromatic aminoketones were synthesized by Mannich reaction. Structures of these compounds were confirmed by 1H NMR, MS and HRMS or element analysis. Pharmacological screening showed that most target compounds inhibited the release of beta-glucuronidase in polymorphonuclear leucocytes by PAF (platelet activating factor) and compounds MA12, MA13, MA18, MA21 and MA33 were more active. The study suggests that target compounds are potential PAF receptor antagonists and their anti-inflammatory activities are due to the inhibition of release of lysosomal enzyme.
Animals ; Anti-Inflammatory Agents ; chemical synthesis ; chemistry ; pharmacology ; therapeutic use ; Arthritis, Rheumatoid ; drug therapy ; Glucuronidase ; metabolism ; Ketones ; chemical synthesis ; chemistry ; pharmacology ; therapeutic use ; Macrophages, Peritoneal ; metabolism ; Mice ; Neutrophils ; enzymology ; Platelet Membrane Glycoproteins ; antagonists & inhibitors ; Rats ; Receptors, G-Protein-Coupled ; antagonists & inhibitors ; Structure-Activity Relationship ; Tumor Necrosis Factor-alpha ; biosynthesis

Anti-Inflammatory Agents ; therapeutic use ; Betamethasone Valerate ; therapeutic use ; Child, Preschool ; Coloring Agents ; adverse effects ; toxicity ; Dermatitis, Allergic Contact ; diagnosis ; drug therapy ; etiology ; Fusidic Acid ; therapeutic use ; Histamine Antagonists ; therapeutic use ; Humans ; Male ; Parenting ; Phenylenediamines ; adverse effects ; toxicity ; Protein Synthesis Inhibitors ; therapeutic use ; Singapore ; Tattooing ; adverse effects ; Time Factors

This study looked into the efficacy of a modified titration protocol of intratympanic gentamicin injection (ITG) in the patients with unilateral intractable Ménière's disease (MD). Modified titration protocol of ITG at a low dose (20 mg/mL) was administered to 10 patients with definite unilateral intractable MD. After initial first two fixed ITGs on weekly basis, the patients might or might not be given any more injections, depending on the appearance of unilateral vestibular loss (UVL). ITG was terminated if the patients satisfied the criteria of UVL. All patients were followed-up for at least two years. The effects of ITG on the vertigo attack, functional level scores and postural balance were evaluated. Of the 10 cases, 8 showed the sign of UVL after receiving initial two ITGs and were not given any more intratympanic injections, and the other 2 patients were administered three ITGs. A two-year follow-up revealed that complete and substantial vertigo control was achieved in 9 cases, and limited vertigo control in 1 patient. Hearing level was lowered in 2 patients. The posture stability and functional level scores were improved. Our study showed that the modified titration protocol of ITG at a low dose could effectively control vertigo in patients with unilateral intractable MD.
Adult ; Drug Administration Schedule ; Ear, Inner ; drug effects ; microbiology ; pathology ; Female ; Follow-Up Studies ; Gentamicins ; therapeutic use ; Hearing ; drug effects ; physiology ; Humans ; Injection, Intratympanic ; Male ; Meniere Disease ; drug therapy ; microbiology ; pathology ; Middle Aged ; Postural Balance ; drug effects ; physiology ; Protein Synthesis Inhibitors ; therapeutic use ; Vertigo ; drug therapy ; microbiology ; pathology