Approaches for the discovery of new cell-penetrating peptides

ABSTRACT

Introduction: The capability of cell-penetrating peptides (CPP), also known as protein transduction domains (PTD), to enter into cells possibly with an attached cargo, makes their application as delivery vectors or as direct therapeutics compelling. They are generally biocompatible, nontoxic, and easy to synthesize and modify. Three decades after the discovery of the first CPPs, ~2,000 CPP sequences have been identified, and many more predicted. Nevertheless, the field has a strong commitment to authenticate new, more efficient, and specific CPPs.

Areas covered: Although a scattering of CPPs have been found by chance, various systematic approaches have been developed and refined over the years to directly aid the identification and depiction of new peptide-based delivery vectors or therapeutics. Here, the authors give an overview of CPPs, and review various approaches of discovering new ones. An emphasis is placed on in silico methods, as these have advanced rapidly in recent years.

Expert opinion: Although there are many known CPPs, there is a need to find more efficient and specific CPPs. Several approaches are used to identify such sequences. The success of these approaches depends on the advancement of others and the successful prediction of CPP sequences relies on experimental data.

KEYWORDS:

• CPP
• HTS
• PTD
• delivery vectors
• CPP prediction

Article highlights

• In silico prediction from both protein and peptide sequences significantly increases the probability of finding new CPPs and reduce the need for extensive in vitro experiments.

• Although new prediction algorithms and approaches are developed, educated guess and trial-and-error approaches retain their importance in discovering new CPPs.

• Predictions rely on known experimental data and there is a need for experimental HTS approaches that increase prediction accuracy and versatility.

• There is no clear-cut strategy to design new CPPs.

• CPPs must be tested and modified for specific applications.

This box summarizes 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 are supported by EU project [2014-2020.4.01.15-0013] from the European Regional Development Fund through the project Center of Excellence in Molecular Cell Engineering.