期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 64, 期 9, 页码 6262-6272出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c00296
关键词
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资金
- NIH [R01 AI143714, R21 AI144552, R01 AI070285]
- Tri-Institutional Therapeutics Discovery Institute
- Weill Cornell Medicine Matching Fund
- Milstein Program in Translational Medicine
- Public Health Service Institutional Research Training Award [T32 AI007180]
Current treatment of tuberculosis (TB) typically lasts at least 6 months, with the latent Mycobacterium tuberculosis (Mtb) being tolerant to most anti-TB drugs. A key hypothesis is that drugs targeting the Mtb proteasome (Mtb20S) may shorten treatment time when used in combination with conventional drugs. A series of macrocyclic peptides, including macrocycle 6, have been developed that selectively target the Mtb20S and have the potential to be developed as anti-TB therapeutics.
Treatment of tuberculosis (TB) currently takes at least 6 months. Latent Mycobacterium tuberculosis (Mtb) is phenotypically tolerant to most anti-TB drugs. A key hypothesis is that drugs that kill nonreplicating (NR) Mtb may shorten treatment when used in combination with conventional drugs. The Mtb proteasome (Mtb20S) could be such a target because its pharmacological inhibition kills NR Mtb and its genetic deletion renders Mtb unable to persist in mice. Here, we report a series of macrocyclic peptides that potently and selectively target the Mtb20S over human proteasomes, including macrocycle 6. The cocrystal structure of macrocycle 6 with Mtb20S revealed structural bases for the species selectivity. Inhibition of 20S within Mtb by 6 dose dependently led to the accumulation of Pup-tagged GFP that is degradable but resistant to depupylation and death of nonreplicating Mtb under nitrosative stress. These results suggest that compounds of this class have the potential to develop as anti-TB therapeutics.
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