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Peptides as the Next Generation Solution for Anti-Infectives

The presence of large-scale manufacturing and advanced synthesis technologies have currently made it possible for the production of even the most complex peptide anti-infectives.

With the possibility of this class of molecules being seen as the next-gen of infectives, safe anti-microbial, as well as with a better understanding of pharmacology and biology, it is just a matter of time before we see the introduction into clinical trials for these promising drug candidates.

This is a vital step in the history and life cycle of peptide anti-infectives and it is one of the strongest indications that the therapeutic and commercial potential of the anti-infectives, is about to be achieved.

In this piece, we will be highlighting the prospects of these agents as the next generation of peptide therapeutics, and will briefly go into some of the challenges that have been faced so far, and some of the lessons that have also been picked along the way.

Antimicrobial Peptides

It is believed that more than 1000 antimicrobial peptides (AMP) have already been identified from various biological sources.

Antimicrobial peptides are known to have a highly attractive therapeutic blueprint, and they have always been seen as potential targets for new generation biological anti-infectives. However, in their own rights, anti-microbial peptides are necessarily “druggable” entities.
This has always presented a huge challenge in the sense that it is never an easy task to develop and commercialize synthetic therapeutic AMP and still have them retain their highly admired anti-microbial attributes.

Apart from this, antimicrobial peptides remain to be extremely viable drug candidates, considering their impressive efficacy, safety, as well as manufacturing and regulatory perspectives.

One of the most hoped-for breakthroughs in the industry, is currently the successful conversion of the therapeutic potential of AMPs into clinical practices.

This is even more relevant given that now is the time when new anti-effective therapies are in great demand considering their clinical and economic significance, as therapies for a variety of conditions and ailments.

At this juncture, it is important to note that there is an unprecedented increase in demand for new and more effective anti-infectives given that there is also an unprecedented increase in the global rates of infections, especially those for major diseases, yet the approval for antimicrobial drugs has been on a sharp decline in the past few years.

Antimicrobial peptides are being viewed as promising candidates for meeting the ever-increasing demand for new classes of anti-infectives owing to their novel modes of operation, and improved safety as well as better efficacy. Of all the peptide drugs that have been approved to-date, it is sad to observe that less than ten of them fall under the category of peptide anti-infectives.

Antimicrobial peptides are known to be pleiotropic. This simply means that apart from being antimicrobial in nature, they also exhibit a range of other properties such as being chemotactic, mitogenic, and proinflammatory.

Additionally, the common challenges usually faced with any peptide drug – these include challenges such as biostability, delivery, bioavailability, and the synthesis of a complicated peptide sequence, usually imply that there has to be a rational refinement of the endogenous peptide forms before they can be used in the formulation of viable peptide anti-infective drug.

However, there have been several previous attempts to formulate and commercialize native antimicrobial peptides, though such attempts did not yield any of the results that we had hoped for. A reason for the failure of such attempts was that there was no good understanding of the complex nature of biology of these defense molecules.

The ongoing studies are hoped to bring in better results, given that there is now a solid and better understanding of the roles and functions of antimicrobial peptides. The research world also now understands better how to use the rational design of synthetic peptides from the templates that were originally developed for the natural antimicrobial peptides – The modification of natural antimicrobial peptides has been completed already, making them potentially viable for drug candidates.

Also, peptide antimicrobials that don’t operate through the traditional AMPs pathways, but can work indirectly such as through the manipulation of the host immune response, are delivering very promising results as potential candidates for anti-infectives.

Research efforts for the successful development of AMP have been hampered in the past, primarily due to commercial limitations that made it exceedingly expensive to acquire goods, produce quality products, and even scale manufacturing efforts.

However, peptide manufacturing has improved greatly in the past few years, and it has become economically viable to produce them on a large scale. This has led to the production of more peptide drugs, an increase in the manufacturers, which have all led to an increase in the availability of the drugs.

At the moment, it is believed that there are at least 20 antimicrobial candidates that have been cleared for the clinical stage of the development. They include selected anti-fungal, antibacterial as well as broader spectrum candidates.

This is good news, but by no means a true reflection of the work that is currently underway in the development of potentially more promising peptide anti-infective candidates.

Below is a brief look at some of the antimicrobial peptides that have been cleared for clinical trials:

Peptide antibiotics
Most of the current research in this field concerning AMPs have had their focus on bacterial infections. Apart from the reasons already explored above, antimicrobial peptides are also attractive when it comes to the treatment of bacterial infections, since we already have various peptide antibiotics being used for clinical applications.

Some of the notable examples include glycopeptides, lipopeptides, and lantibiotics. All of these peptide antibiotics are currently being used for dealing with human infections. It can be argued that the most common peptide being prescribed as peptide antibiotics, are colistin and vancomycin.

With some peptide antibiotics, the disruption of the membrane is not necessary for them to be effective. This is unlike most AMPs where membrane disruption is necessary, and which have a very specific target interaction in their mode of operation.

Antimicrobial AMPs in Clinical Trials

It is true that there is considerable interest in the development of AMPs as anti-infectives, a huge focus has always been on developing AMPs as antimicrobial agents.

At the moment, there are hundreds, if not thousands of AMPs in clinical trials, and here is a brief look at some of the most notable ones, and ones which have shown very good progress in most of the clinical trials:

Pexiganan – this is a 22-amino acid AMP. It is one of the analogs of the maganin peptides, with its major source usually being the skin of the African clawed frog. It has shown potential for broad-spectrum membranolytic activity against certain clinical isolates such as those of gram-negative and gram-positive bacteria. The history of Pexiganan is relatively long, given that it was first used during the early 1990s, and since its form or any of its variants have always been in the form of some clinical trials.

Iseganan – this is a 17-amino acid protegrin I analog. Several studies and clinical trials have shown this amino acid has a broad spectrum of antimicrobial activities against pathogens such as viruses, fungi, and certain bacteria.

Though very good results were obtained from the initial development of Iseganan, the development hit a halt in 2004 after the Phase III trials on oral mucositis failed to yield the results as had been postulated. However, the research on the peptide commenced again in 2010 with the use of Ardea’s protegrin derived protein epitope mimemic instead.

This protein epitope mimemic showed that it could destroy P. aeruginosa bacteria, and sadly enough, it could not kill any other bacteria.

Brilacidin – this is a membranolytic defensing, and it has been discovered to have rapid bactericidal activity against gram-negative and gram-positive pathogens. It was very successful in Phase II clinical trials, in the treatment of patients with ABSSSI – a condition normally caused by S. aureus. It showed consistently high clinical response rates. Additionally, it was also safe and was generally well-tolerated by most of the patients.

The other notable AMPs that are still in clinical trials include Lytixar. This is a broad spectrum synthetic peptidomimetic that has a very powerful membranolytic mechanism course of action. It is in late-stage pre-clinical development, and it is being formulated to be a topical agent used for the treatment of infections occasioned by pathogens, such as P. aeruginous and S. aureus.

Anti-fungal peptides

The developments in anti-fungal peptide research are not as advanced as that of antimicrobial peptides. At the moment, there are only four anti-fungal peptides that have been greenlighted to get into clinical trials. Apart from this limited number, the in vivo data from animal studies is also limited, and this has always caused a major challenge in trying to determine the efficacy of some of the antifungal peptides.

Synthetic antifungal peptides based on mammalian structures

It is important to point out that Novexatin is the most successful antifungal peptide we have had to this date. These peptides are derived from or based on human or other mammalian peptide structures.

The other peptides in this category have demonstrated very promising preclinical potential against a wide range of pathogens. Most of these other peptides are based on the c-terminal components of the endogenous AMPs histatin.

They have proven to be very effective against pathogens such as Candida albicans, where they have displayed deadly membrane-disrupting fungicidal capabilities.

There has been considerable discussion about the potential for human health application of PAF26. This is a broad spectrum antimicrobial hexapeptide, which was initially believed to possess great activity against fungal phytopathogens.

When an N-terminal tryotophan was added to the peptide, it was observed that there was a significant increase in the antifungal activity of the peptide. This is a penetratin-like peptide that is complete with cell-penetrating properties, except it is nonlytic – this simply means that its mode of action is likely to lead to a dose-dependent accumulation of reactive nitric oxide in fungal cells.

Apart from histatin, there are other variants of salivary peptides that have been researched and thoroughly investigated for their potential as candidates for clinical trials. It should be remembered that most of the peptides obtained from the N-terminus region of the human salivary mucin have fungicidal properties against pathogens such as C. albicans and other various human fungal pathogens.

Antifungal peptides from marine sources

Mollusks and other sea creatures have been identified by researchers to have potential clinical interests. Some of these AMPs include mytimycin, which is an antifungal peptide that was originally obtained from blue mussel in 1996.

Through the process of back translation, it was possible to identify the partial 33-amino acid sequence. The process also helped to identify other putative mytimycin-related peptides, which are also believed to have some incredible therapeutic potential.

Another promising antifungal peptide obtained from a marine source is Cm-p1. This is a ten-amino acid that was originally obtained from the crude extract of the marine snail. Cm-p1 is a helical peptide that has shown inhibitory activities against numerous filamentous fungi and some yeasts that are known to be relevant to human health. This was also one of the few marine peptides that were discovered to not be toxic towards mammalian cells when administered as therapeutic doses.

Amphibian AMPs with antifungal activity

The Maganins were the very first amphibian AMPs to be isolated from the African Clawed frog. The potential of maganins being applied in the pharmaceutical industry was the main reason for the establishment of Maganin Pharmaceuticals. The company has been involved in a variety of clinical trials, with some being successful, but the majority of them have not led to the anticipated results.

Maganin Pharmaceuticals

Currently, the company is heavily involved with work on the next generation of related structures, designed for antifungal applications. With a better understanding and improved biotechnology, it has been discovered that Maganins have even more potent antifungal activities than most of the amphibian AMPs that keep on getting discovered with each passing day.

It is hoped that with time, the clinical trials will be ready, and hopefully, science and technology will be able to conquer the field of AMP peptides, giving way to the formulation and manufacture of a variety of potent antimicrobial and antifungal drugs.

References

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  • Romanova, G. A., et al. “Neuroprotective and Antiamnesic Effects of Semax during Experimental Ischemic Infarction of the Cerebral Cortex.” Bulletin of Experimental Biology and Medicine, vol. 142, no. 6, Dec. 2006, pp. 663–666, 10.1007/s10517-006-0445-0.
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  • Umarova, B. A., et al. “Secretory Activity of Mast Cell during Stress: Effect of Prolyl-Glycyl-Proline and Semax.” Bulletin of Experimental Biology and Medicine, vol. 136, no. 4, Oct. 2003, pp. 325–327, 10.1023/b:bebm.0000010942.14275.50.
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  • Medvedeva, Ekaterina V, et al. “The Peptide Semax Affects the Expression of Genes Related to the Immune and Vascular Systems in Rat Brain Focal Ischemia: Genome-Wide Transcriptional Analysis.” BMC Genomics, vol. 15, no. 1, 2014, p. 228, 10.1186/1471-2164-15-228.
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