Novel approaches for designing drugs that interfere with pH regulation

ABSTRACT

Introduction: In all living species, pH regulation is a tightly controlled process, with a plethora of proteins involved in its regulation. These include sodium-proton exchangers, carbonic anhydrases, anion exchangers, bicarbonate transporters/cotransporters, H⁺-ATPases, and monocarboxylate transporters. All of them play crucial roles in acid-base balancing, both in eukaryotic as well as in prokaryotic organisms, making them interesting drug targets for the management of pathological events (in)directly involved in pH regulation.

Areas covered: Interfering with pH regulation for the treatment of tumors and microbial infections is the main focus of this review, with particular attention paid to inhibitors targeting the above-mentioned proteins. The latest advances in each field id reviewed.

Expert opinion: Interfering with the pH regulation of tumor cells is a validated approach to tackle primary tumors and metastases growth. Carbonic anhydrases are the most investigated proteins of those aforementioned, with several inhibitors in clinical development. Recent advances in the characterization of proteins involved in pH homeostasis of various pathogens evidenced their crucial role in the survival and virulence of bacterial, fungal, and protozoan microorganisms. Some encouraging results shed light on the possibility to target such proteins for obtaining new anti-infectives, overcoming the extensive drug resistance problems of clinically used drugs.

KEYWORDS:

• pH modulation
• tumors
• antimicrobial agents
• drug discovery
• Warburg effect

Article highlights

• Maintenance an optimal intra-/axtra-cellular pH is tightly regulated in all cells.

• pH is regulated in a dynamic equilibrium by several proteins such as carbonic anhydrases (CAs), anion exchangers, bicarbonate transporters/cotransporters, H⁺-ATPases, monocarboxylate transporters, both in eukaryotic and prokaryotic organisms.

• the acidic tumor microenvironment is due to the high aerobic glycolysis rate (Warburg effect). Proteins involved in the maintenance of such an altered pH gradient were proposed to be targeted for novel antitumor and diagnostic agents.

• A ‘Warburg-like metabolism’ is also present in activated lymphocytes, due to infection with intracellular pathogens. This metabolic reprogramming contributes to the pathogen survival and virulence and has been proposed to be targeted by novel anti-infectives.

• The characterization of pathogen proteins involved in pH regulation makes then attracting targets for antibacterial/antifungal/antiprotozoan therapy.

• CAs from pathogens are specifically involved in the regulation of their microenvironment and as a consequence, their inhibition was found to be exploitable for designing new antimicrobial strategies.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was not funded.