Structure-based design and synthesis of macrocyclic human rhinovirus 3C protease inhibitors.

Namoto, Kenji; Sirockin, Finton; Sellner, Holger; Wiesmann, Christian; Villard, Frederic; Moreau, Robert J; Valeur, Eric; Paulding, Stephanie C; Schleeger, Simone; Schipp, Kathrin; Loup, Joachim; Andrews, Lori; Swale, Ryann; Robinson, Michael; Farady, Christopher J

Namoto, Kenji; Sirockin, Finton; Sellner, Holger; Wiesmann, Christian; Villard, Frederic; Moreau, Robert J; Valeur, Eric; Paulding, Stephanie C; Schleeger, Simone; Schipp, Kathrin; Loup, Joachim; Andrews, Lori; Swale, Ryann; Robinson, Michael; Farady, Christopher J.

Affiliation

Namoto K; Novartis Institutes for BioMedical Research, Novartis Campus, CH-4002 Basel, Switzerland. Electronic address: kenji.namoto@novartis.com.
Sirockin F; Novartis Institutes for BioMedical Research, Novartis Campus, CH-4002 Basel, Switzerland.
Sellner H; Novartis Institutes for BioMedical Research, Novartis Campus, CH-4002 Basel, Switzerland.
Wiesmann C; Novartis Institutes for BioMedical Research, Novartis Campus, CH-4002 Basel, Switzerland.
Villard F; Novartis Institutes for BioMedical Research, Novartis Campus, CH-4002 Basel, Switzerland.
Moreau RJ; Novartis Institutes for BioMedical Research, 5300 Chiron Way, Emeryville, CA 94608-2916, USA.
Valeur E; Novartis Institutes for BioMedical Research, Novartis Campus, CH-4002 Basel, Switzerland.
Paulding SC; Novartis Institutes for BioMedical Research, Novartis Campus, CH-4002 Basel, Switzerland.
Schleeger S; Novartis Institutes for BioMedical Research, Novartis Campus, CH-4002 Basel, Switzerland.
Schipp K; Novartis Institutes for BioMedical Research, Novartis Campus, CH-4002 Basel, Switzerland.
Loup J; Novartis Institutes for BioMedical Research, Novartis Campus, CH-4002 Basel, Switzerland.
Andrews L; Novartis Institutes for BioMedical Research, 5300 Chiron Way, Emeryville, CA 94608-2916, USA.
Swale R; Novartis Institutes for BioMedical Research, 5300 Chiron Way, Emeryville, CA 94608-2916, USA.
Robinson M; Novartis Institutes for BioMedical Research, 5300 Chiron Way, Emeryville, CA 94608-2916, USA.
Farady CJ; Novartis Institutes for BioMedical Research, Novartis Campus, CH-4002 Basel, Switzerland. Electronic address: christopher.farady@novartis.com.

Bioorg Med Chem Lett ; 28(5): 906-909, 2018 03 01.

Article in En | MEDLINE | ID: mdl-29433930

ABSTRACT

ABSTRACT

The design and synthesis of macrocyclic inhibitors of human rhinovirus 3C protease is described. A macrocyclic linkage of the P1 and P3 residues, and the subsequent structure-based optimization of the macrocycle conformation and size led to the identification of a potent biochemical inhibitor 10 with sub-micromolar antiviral activity.

Subject(s)

Antiviral Agents/pharmacology; Cysteine Proteinase Inhibitors/pharmacology; Drug Design; Macrocyclic Compounds/pharmacology; Rhinovirus/drug effects; Viral Proteins/antagonists & inhibitors; 3C Viral Proteases; Antiviral Agents/chemical synthesis; Antiviral Agents/chemistry; Crystallography, X-Ray; Cysteine Endopeptidases/metabolism; Cysteine Proteinase Inhibitors/chemical synthesis; Cysteine Proteinase Inhibitors/chemistry; Dose-Response Relationship, Drug; Humans; Macrocyclic Compounds/chemical synthesis; Macrocyclic Compounds/chemistry; Microbial Sensitivity Tests; Models, Molecular; Molecular Conformation; Rhinovirus/enzymology; Structure-Activity Relationship; Viral Proteins/metabolism

Key words

Covalent inhibitor; Macrocycle; Protease inhibition; Rhinovirus 3C protease; Solid phase synthesis; Structure-based drug design

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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Antiviral Agents / Rhinovirus / Viral Proteins / Drug Design / Cysteine Proteinase Inhibitors / Macrocyclic Compounds Limits: Humans Language: En Journal: Bioorg Med Chem Lett Journal subject: BIOQUIMICA / QUIMICA Year: 2018 Type: Article

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