Structure-Guided Drug Design of 6‑Substituted Adenosine Analogues as Potent Inhibitors of Mycobacterium tuberculosis Adenosine Kinase

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.