Signal peptide peptidase: a potential therapeutic target for parasitic and viral infections

ABSTRACT

Introduction

Signal peptide peptidase (SPP) is a GxGD-type intramembrane-cleaving aspartyl protease responsible for clearing accumulating signal peptides in the endoplasmic reticulum. SPP is conserved among all kingdoms and is essential for maintaining cell homeostasis. Inhibition of SPP with selective inhibitors and the structurally similar HIV protease inhibitors results in signal peptide accumulation and subsequent cell death. Identification of SPP homologues in major human parasitic infections has opened a new therapeutic opportunity. Moreover, the essentiality of mammalian SPP-mediated viral protein processing during infection is emerging.

Areas Covered

This review introduces the discovery and biological function of human SPP enzymes and identify parasitic homologues as pharmacological targets of both SPP and HIV protease inhibitors. Later, the role of mammalian SPP during viral infection and how disruption of host SPP can be employed as a novel antiviral therapy are examined and discussed.

Expert Opinion

Parasitic and viral infections cause severe health and economic burden, exacerbated by the lack of new therapeutics in the pipeline. SPP has been shown to be essential for malaria parasite growth and encouraging evidence in other parasites demonstrates broad essentiality of these proteases as therapeutic targets. As drug resistant parasite and viruses emerge, SPP inhibition will provide a new generation of compounds to counter the growing threat of antimicrobial resistance.

KEYWORDS:

• Babesiosis
• HIV protease inhibitor
• leishmania
• lopinavir
• malaria
• trypanosoma
• signal peptide peptidase

Article Highlights

• Plasmodium falciparum encodes a single SPP orthologue (PfSPP)

• The SPP gene is essential for malaria parasite growth and its homologues in other parasites thus demonstrating critical and broad essentiality of these proteases as therapeutic targets.

• Babesia microti infection was recently shown to be sensitive to SPP inhibition through (ZLL)2 ketone and HIV protease inhibitors in both intraerythrocytic and in mouse models of infection.

• The neglected tropical diseases Leishmaniasis and Chagas disease may be treatable through SPP inhibition, as population studies where HIV protease inhibitor treatment is high showed diminished parasite co-infection with HIV.

• Several parasite SPP genes are predicted but have not been validated biochemically, providing an exciting opportunity to develop specific novel inhibitors against these enzymes.

• Several human viruses take advantage of host cellular SPP during their infective lifecycle utilizing the enzyme in viral processing and propagation mainly through interaction with surface glycoproteins and capsid proteins.

• Future investigations could yield a repertoire of highly selective and potent inhibitors of parasite and viral SPPs in preclinical models (including rodents and non-human primates).

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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

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

The authors are funded by the National Institutes of Health-NHLBI-HL060961, USA