Structure-guided design of potent and permeable inhibitors of MERS coronavirus 3CL protease that utilize a piperidine moiety as a novel design element

Autor: Scott Lovell, Vishnu C. Damalanka, Kyeong-Ok Chang, William C. Groutas, Anthony R. Fehr, A.D. Rathnayake, Stanley Perlman, N. Mehzabeen, Gerald H. Lushington, Yunjeong Kim, Anushka C. Galasiti Kankanamalage, Kevin P. Battaile
Rok vydání: 2018
Předmět:
Models
Molecular
0301 basic medicine
Middle East respiratory syndrome coronavirus
viruses
medicine.medical_treatment
030106 microbiology
Cysteine Proteinase Inhibitors
Crystallography
X-Ray
medicine.disease_cause
Antiviral Agents
Article
Structure-Activity Relationship
Viral Proteins
03 medical and health sciences
chemistry.chemical_compound
Piperidines
Chlorocebus aethiops
Drug Discovery
medicine
Animals
Moiety
Vero Cells
Cells
Cultured
Pharmacology
Protease
Cell Death
Dose-Response Relationship
Drug
Molecular Structure
Chemistry
Organic Chemistry
3C Viral Proteases
Biological activity
General Medicine
Combinatorial chemistry
Small molecule
3. Good health
Cysteine Endopeptidases
030104 developmental biology
Mechanism of action
Viral replication
Drug Design
Cats
Middle East Respiratory Syndrome Coronavirus
Piperidine
medicine.symptom
Zdroj: European Journal of Medicinal Chemistry
ISSN: 0223-5234
DOI: 10.1016/j.ejmech.2018.03.004
Popis: There are currently no approved vaccines or small molecule therapeutics available for the prophylaxis or treatment of Middle East Respiratory Syndrome coronavirus (MERS-CoV) infections. MERS-CoV 3CL protease is essential for viral replication; consequently, it is an attractive target that provides a potentially effective means of developing small molecule therapeutics for combatting MERS-CoV. We describe herein the structure-guided design and evaluation of a novel class of inhibitors of MERS-CoV 3CL protease that embody a piperidine moiety as a design element that is well-suited to exploiting favorable subsite binding interactions to attain optimal pharmacological activity and PK properties. The mechanism of action of the compounds and the structural determinants associated with binding were illuminated using X-ray crystallography.
Databáze: OpenAIRE
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