ABSTRACT
Mycobacterium tuberculosis adenosine kinase (MtbAdoK) is an essential enzyme of Mtb and forms part of the purine salvage pathway within mycobacteria. Evidence suggests that the purine salvage pathway might play a crucial role in Mtb survival and persistence during its latent phase of infection. In these studies, we adopted a structural approach to the discovery, structure-guided design, and synthesis of a series of adenosine analogues that displayed inhibition constants ranging from 5 to 120 nM against the enzyme. Two of these compounds exhibited low micromolar activity against Mtb with half maximal effective inhibitory concentrations of 1.7 and 4.0 µM. Our selectivity and preliminary pharmacokinetic studies showed that the compounds possess a higher degree of specificity against MtbAdoK when compared with the human counterpart and are well tolerated in rodents, respectively. Finally, crystallographic studies showed the molecular basis of inhibition, potency, and selectivity and revealed the presence of a potentially therapeutically relevant cavity unique to the MtbAdoK homodimer.
Subject(s)
Adenosine Kinase/metabolism , Adenosine/analogs & derivatives , Drug Design , Mycobacterium tuberculosis/enzymology , Protein Kinase Inhibitors/chemical synthesis , Adenosine/metabolism , Adenosine/pharmacokinetics , Adenosine Kinase/chemistry , Animals , Antitubercular Agents/chemical synthesis , Antitubercular Agents/metabolism , Antitubercular Agents/pharmacokinetics , Catalytic Domain , Female , Mice , Molecular Structure , Protein Binding , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/pharmacokinetics , Structure-Activity RelationshipABSTRACT
A new class of inhibitors for cysteine proteases cathepsin B, L, K and S is described. These inhibitors are based on the beta-lactam ring designed to interact with the nucleophilic thiol of the cysteine in the active site of cysteine proteases. Some 3-acylamino-azetidin-2-one derivatives showed very potent inhibition activities for cathepsins L, K and S at the nanomolar or subnanomolar IC(50) values.
Subject(s)
Azetidines/chemical synthesis , Cysteine Proteinase Inhibitors/chemical synthesis , Azetidines/pharmacology , Cathepsin B/antagonists & inhibitors , Cathepsin K , Cathepsin L , Cathepsins/antagonists & inhibitors , Cysteine Endopeptidases , Cysteine Proteinase Inhibitors/pharmacology , Drug Design , Humans , Inhibitory Concentration 50 , Lactams/chemistry , Leukocyte Elastase/antagonists & inhibitors , Structure-Activity RelationshipABSTRACT
A series of 6-substituted amino-4-oxa-1-azabicyclo[3,2,0]heptan-7-one compounds was designed and synthesized as a new class of inhibitors for cysteine proteases cathepsins B, L, K, and S. One compound (5S,6S)-6-(N-benzyloxycarbonyl-L-phenylalanyl) amino-4-oxa-1-azabicyclo[3,2,0]heptan-7-one showed excellent cathepsin L and K inhibition activity with IC(50) at a low nanomolar range.
Subject(s)
Cysteine Proteinase Inhibitors/chemical synthesis , Cysteine Proteinase Inhibitors/pharmacology , Lactams/chemistry , Lactams/pharmacology , Cathepsins/antagonists & inhibitors , Drug Design , Inhibitory Concentration 50 , Models, Molecular , Papain/antagonists & inhibitors , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The synthesis of a new series of 6-acylamino penam derivatives and their inhibition of cysteine proteases cathepsins B, L, K, and S is described. The 6-acylamino-penam sulfone compounds showed excellent cathepsin L, K, and S inhibition activity with IC(50) values in the nanomolar and subnanomolar range.
