BacPROTACs targeting Clp protease: a promising strategy for anti-mycobacterial drug discovery

Author(s)

Bonjorno, Andressa Francielli ; Pavan, Aline Renata ; Fernandes, Guilherme F. S. ; Scarim, Caue Benito ; Castagnolo, Daniele ; Dos Santos, Jean Leandro

• Document type: Journal article
• Source: RONTIERS IN CHEMISTR; v. 12, p. 6-pg., 2024-01-31.

Abstract

Tuberculosis (TB) has claimed more lives over the course of two millennia than any other infectious disease worldwide. In 2021, the World Health Organization (WHO) estimated that 10.6 million people were diagnosed with TB, resulting in the deaths of 1.4 million HIV-negative individuals. The emergence of multidrug-resistant TB (MDR-TB), defined as resistance to at least rifampicin (RIF) and isoniazid (INH), and extensively drug-resistant TB (XDR-TB), poses the primary challenge to overcome in the coming years. We have recently conducted an extensive analysis of investments and research endeavours in the field, with the overarching objective of achieving the established milestone of TB eradication by the year 2030. Over the past several years, there has been notable progress in advancing a multitude of promising compounds, each possessing distinct mechanisms of action, into clinical phases of development. However, it is worth noting that strains of mycobacteria resistant to current antitubercular drugs have already emerged for some of these compounds The exploration of the innovative Proteolytic Target Chimeras (PROTACs) protein degradation approach has emerged as a viable avenue for the discovery of novel antimicrobials. While the ubiquitin system is exclusive to eukaryotic cells, certain bacteria use a similar degradation system that relies on the recognition of phosphorylated arginine residues (pArg) by the ClpC:ClpP (ClpCP) protease, thereby leading to protein degradation. In this opinion article, we have described and analized the advances in the use of PROTACs that leverage bacterial proteolytic machinery (BacPROTACs) to design new antitubercular agents. Scope Statement. The development of novel pharmaceuticals for tuberculosis treatment is deemed urgently necessary due to the emergence of resistant strains. In this context, the introduction of new technologies capable of alleviating the disease and attaining the objectives outlined by the World Health Organization is imperative. Among the innovative strategies, the degradation of proteins that are crucial for the survival of the bacillus holds promise for generating new medications, particularly those that are effective at treating latent (non-replicating) Mycobacterium tuberculosis. Within this perspective, we present the advancements and obstacles encountered in the exploration of new BacPROTAC compounds, with the intention of encouraging research and illuminating challenges associated with the implementation of BacPROTACs to address to the global tuberculosis crisis. (AU)

• FAPESP's process: 20/13279-7 - Synthesis and anti-Mycobacterium tuberculosis evaluation of new nitroimidazooxazine derivatives useful for the treatment of multidrug-resistant tuberculosis
• Grantee: Jean Leandro dos Santos
• Support Opportunities: Regular Research Grants
• FAPESP's process: 21/14973-7 - Synthesis and evaluation of new nitroimidazooxazine derivatives designed to act against drug-resistant Mycobacterium tuberculosis
• Grantee: Andressa Francielli Bonjorno
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 22/15844-9 - Synthesis and evaluation of BacPROTACs designed as anti-Mycobacterium tuberculosis agents
• Grantee: Andressa Francielli Bonjorno
• Support Opportunities: Scholarships abroad - Research Internship - Master's degree
• FAPESP's process: 23/05739-6 - Strategies for intervention in gamma-globin gene repressor complexes containing Histone Deacetylase (HDAC-1 and HDAC-2) using small molecules
• Grantee: Jean Leandro dos Santos
• Support Opportunities: Regular Research Grants
• FAPESP's process: 18/19523-7 - Design, synthesis and pharmacological evaluation of hydroxyurea derivatives designed as histone deacetylase inhibitors for Sickle Cell Anemia
• Grantee: Aline Renata Pavan
• Support Opportunities: Scholarships in Brazil - Doctorate