Chapter 3.9 - CD73 (5′-Ectonucleotidase)

Abstract

5′-Ectonucleotidase (e5NT), a metalloenzyme also known as CD73, hydrolyzes AMP to phosphate and adenosine. In mammalians, CD73 is involved in several physiological and pathological processes, among which immune homeostasis, inflammation, and tumor progression. In bacteria, e5NTs are found in the periplasmic space, cytoplasm, or are connected to the outer membrane. Interestingly, the bacterial membrane-associated and periplasmic 5′-NTs have been linked to an enhanced microbial virulence and pathogenicity. The past decade saw the development of small-molecule and monoclonal antibodies (MAbs) acting as mammalian CD73 inhibitors in the search of novel immunotherapeutic agents for the management of many tumor types. CD73 X-ray crystal structure, alone as well as in complex with a nonhydrolyzable adenosine diphosphate (ADP) analog, adenosine (α,β)-methylene diphosphate (AMPCP), but also with other types of inhibitors, have been used to design effective nucleotide/nucleoside-based human CD73 inhibitors. Nonnucleotide CD73 inhibitors were also reported. One of the most effective in vitro small-molecule CD73 inhibitors, known as AB680, is nowadays in clinical trials as an immunotherapeutic antitumor agent with a new mechanism of action. In bacteria, even if CD73 is considered as a potential target for developing inhibitors with pharmacological action as antibacterials, few drug design studies have been reported. Thus, scientists are encouraged to pursue inhibitors of human and bacterial 5-NTs as a possible solution to the perplexing problems of cancer and antibiotic resistance, respectively, as discussed in this chapter.