title: Characterization of 2-hydroxy-1-naphthaldehyde isonicotinoyl hydrazone as a novel inhibitor of methionine aminopeptidases from Mycobacterium tuberculosis.
abstract: Mycobacterium tuberculosis (Mtb) and the Human Immunodeficiency Virus (HIV) pose a major public health threat. The 2015 World Health Organization (WHO) report estimates that one in three HIV deaths is due to Mtb, the causative agent of Tuberculosis (TB). The lethal synergy between these two pathogens leads to a decline in the immune function of infected individuals as well as a rise in morbidity and mortality rates. The deadly interaction between TB and HIV, along with the heightened emergence of drug resistance, drug-drug interactions, reduced drug efficacy and increased drug toxicity, has made the therapeutic management of co-infected individuals a major challenge. Hence, the development of new drug targets and/or new drug leads are imperative for the effective therapeutic management of co-infected patients. Here, we report the characterization of 2-hydroxy-1-naphthaldehyde isonicotinoyl hydrazone (311), a known inhibitor of HIV-1 replication and transcription as a new inhibitor of methionine aminopeptidases (MetAPs) from Mycobacterium tuberculosis: MtMetAP1a and MtMetAP1c. MetAP is a metalloprotease that removes the N-terminal methionine during protein synthesis. The essential role of MetAP in microbes makes it a promising chemotherapeutic target. We demonstrated that 311 is a potent and selective inhibitor of MtMetAP1a and MtMetAP1c. Furthermore, we found that 311 is active against replicating and aged non-growing Mtb at low micromolar concentrations. These results suggest that 311 is a promising lead for the development of novel class of therapeutic agents with dual inhibition of TB and HIV for the treatment of TB-HIV co-infection.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX 77004, USA.
authors.forename: Sarah F
authors.initials: SF
authors.lastname: John
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX 77004, USA.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Aniemeke
authors.affiliation: Department of Pathology and Genomic Medicine, The Methodist Hospital Research Institute, Houston, TX 77030, USA.
authors.forename: Ngan P
authors.initials: NP
authors.lastname: Ha
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Curtis R
authors.initials: CR
authors.lastname: Chong
authors.affiliation: Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Peihua
authors.initials: P
authors.lastname: Gu
authors.affiliation: Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Neurosurgery, Yale University, New Haven, CT 06510, USA.
authors.forename: Jiangbing
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Genomic Medicine, The Methodist Hospital Research Institute, Houston, TX 77030, USA.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Graviss
authors.affiliation: Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA. Electronic address: joliu@jhu.edu.
authors.forename: Jun O
authors.initials: JO
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX 77004, USA. Electronic address: olaleyeoa@tsu.edu.
authors.forename: Omonike A
authors.initials: OA
authors.lastname: Olaleye
mesh_terms: D000626:Aminopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019380:Anti-HIV Agents / Q000494:pharmacology; D000995:Antitubercular Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D060085:Coinfection; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D057166:High-Throughput Screening Assays; D006801:Humans; D007538:Isoniazid / Q000494:pharmacology; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D014376:Tuberculosis / Q000188:drug therapy* / Q000382:microbiology
chemical_list: C120275:2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone; D019380:Anti-HIV Agents; D000995:Antitubercular Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D000626:Aminopeptidases; D007538:Isoniazid
keywords: Co-infection; Drug discovery; Drug interactions; Drug screening; HIV; TB