An overview of ProTide technology and its implications to drug discovery

ABSTRACT

Introduction: The ProTide technology is a phosphate (or phosphonate) prodrug method devised to deliver nucleoside monophosphate (or monophosphonate) intracellularly bypassing the key challenges of antiviral and anticancer nucleoside analogs. Three new antiviral drugs, exploiting this technology, have been approved by the FDA while others are in clinical studies as anticancer agents.

Areas covered: The authors describe the origin and development of this technology and its incredible success in transforming the drug discovery of antiviral and anticancer nucleoside analogues. As evidence, discussion on the antiviral ProTides on the market, and those currently in clinical development are included. The authors focus on how the proven capacity of this technology to generate new drug candidates has stimulated its application to non-nucleoside-based molecules.

Expert opinion: The ProTide approach has been extremely successful in delivering blockbuster antiviral medicines and it seems highly promising in oncology. Its application to non-nucleoside-based small molecules is recently emerging and proving effective in other therapeutic areas. However, investigations to explain the lack of activity of certain ProTide series and comprehensive structure activity relationship studies to identify the appropriate phosphoramidate motifs depending on the parent molecule are in our opinion mandatory for the future development of these compounds.

KEYWORDS:

• ProTide
• phosphor(n)amidate
• prodrugs
• pro-nucleotide
• nucleoside analogues
• anticancer
• antiviral

Article highlights

• Among different phosphate prodrug approaches, the proTide technology has shown to be superior in the delivery of the monophosphate species of therapeutic nucleoside analogues.

• Extensive preclinical studies in the antiviral and anticancer fields produced three FDA- approved antiviral drugs and three clinical candidates currently investigated as anticancer agents.

• More investigations are needed to explain why the ProTide approach was no so effective when applied to certain nucleoside analogues as it was on others.

• There are strong evidence supporting the dependence of ProTide intracellular metabolism by the phosphorus stereochemistry. Therefore, the development of a robust and wide applicability diastereoselective synthetic methodologies is strongly needed.

• Although L-alanine is the amino acid of choice for ProTide of nucleoside analogues when this technology is applied to non-nucleoside substrates, other amino acids have given better results in term of activity, activation, and stability.

• Phosphoramidates of non-nucleoside substrates share the same activation pathway of their nucleoside analogues counterparts. This suggests the potential application of this technology to a wider range of substrates with other therapeutic applications.

The box summarizes the key points contained in the article.

Declaration of interest

The authors have no other 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 apart from those disclosed.

Reviewer Disclosures

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

Additional information

Funding

The authors declare being recipients of the following financial support for research, authorship, and/or publication of this article: Chris McGuigan’s laboratory at Cardiff University, who provided the basis for ProTide Technology, actively collaborated with Inhibitex inc., and Bristol-Myers Squibb (whose agent INX-08189 is discussed herein), NuCana PLC (whose agents Accelerin, NUC3373 and NUC7738 received financial support for their development) and Bioberica who sponsored the work on N-acetylglucosamine phosphoramidates. Furthermore, F Pertusati has received financial support from Cerecor (Ichorion Therapeutics and Demeter Therapeutics) for the development of CERC-193 and Ac₃-N-acetyl mannosamine phosphoramidates.