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European Biopharmaceutical Review

Top Class Templates

 

Peptides offer a therapeutic step-change in our approach to tackling difficult to treat infections, and advances in manufacturing techniques make these molecules a particularly attractive option for the next generation of antimicrobials.

Biologics-based strategies for the discovery of novel anti-infective drug candidates are showing increasing promise as a means to generating more effective and safer antibacterial, antiviral and antifungal treatments. In particular, a better understanding of the role, regulation and mode of action of antimicrobial peptides – the body’s first line of defence against infection – points to these molecules as ideal therapeutic templates for the design of a new class of anti-infectives. Taken together with recent advances in peptide manufacturing techniques and capabilities, these molecules are not only theoretically attractive therapeutic candidates, but a commercially viable option as well.

New Biotechnology versus Big Pharma Approaches of Old

Small-molecule chemistry and traditional screening approaches are now failing to make much, if any, headway in the development of new classes of anti-infective therapies. Conversely, recent exciting advances in biological therapeutic approaches suggest that peptide, protein, antibody and other drug classes engineered from the body’s own host defence mechanisms for fighting infection may reinvigorate our armoury of antibacterials, antifungal and antiviral weapons in the future. These molecules are not just reformulations or other adaptations of existing small molecule antimicrobial drug classes, but novel therapeutics designed from firstprinciples. As such, these have distinct activity/mode of action and the potential for superior activity and clinical performance to their predecessors.

The Need for New Anti-Infective Drugs

There has been a dramatic decline in new anti-infective drug approvals in the last three decades (see Figure 1) (1-3). At the same time, global infection rates and emerging pathogens continue to increase (2-7). The usefulness of our existing war chest of antimicrobials in this challenging clinical and regulatory climate is ever more limited, effectively having been exhausted after decades of over-use and inappropriate prescribing practices (see Figure 2). Options in antibacterial treatments still outnumber – and provide additional clinical ‘safety nets’ – than antifungal and antiviral therapy strategies. Nonetheless, infectious disease remains responsible for one third of global mortality rates (4-7).

The requirement for new antimicrobials provides a significant commercial opportunity; the global anti-infectives market is set to be worth in excess of $100 billion per annum in the next few years (8,9). Anti-infective research within the industry has most certainly been re-invigorated of late, reflecting no doubt both the clinical problem and market potential. The innovation in new anti-infective drug development has been derived largely from biotechnology rather than pharmaceutical companies.

With the current and predicted future need for new antimicrobials in mind, it’s imperative that the potential of a sufficient number of these and future drug candidates is converted to clinical success and eventual medical practice. The next generation of antimicrobials must also ‘deliver’ in ways beyond the scope of their small molecule predecessors/counterparts to be successful in combating the most challenging of infections, and in being able to kill pathogenic microbes in the most complex of biological systems. For example, they should be able to combat drug or antibiotic insensitive fungal and bacterial pathogens, as well as penetrate bacterial and fungal biofi lms, inhibiting viral entry into cells and killing metabolically inactive plus metabolising microbes.

Developing these new therapeutic candidates therefore involves demonstrating not just that they are interesting antimicrobials in vitro, but that they function optimally in situ within the tissues wherein their target pathogens reside. Because biologic approaches are based on components of the body’s immune response, they are able to do this.

It may seem like a tall order to develop new anti-infective therapies with all of these attributes, but nature has already provided a platform for this: one comprising molecules that are an exact fi t for future antibiotics requirements and a system that has been developed and refi ned in all eukaryotic organisms (and some prokaryotes) over the past two billion years.

Nature’s Antibiotics

Antimicrobial peptides provide the body’s fi rst line of defence against infection from opportunistic pathogens (11-14). Produced at the interfaces between the internal and external environment (skin, nails, epithelial linings of the respiratory, gastrointestinal and urogenital tracts) and by neutrophils, these ancient, highly evolutionarily conserved innate immune effector molecules have an elegantly simple mode of microbicidal action which neutralises target pathogens through deleterious interactions with membrane components, resulting in perturbation and/or lysis of target microbes, or an inability to replicate or enter target mammalian cells (11-14).

Antimicrobial peptides target metabolically active and also nonmetabolising microorganisms (11-14) – a major advantage over most current antimicrobial agents which are active only against replicating microbes. This mode of action is also why the chance of acquired resistance developing is negated, if not minimised (11-16). Antimicrobial peptides also outperform most conventional small molecule synthetic therapeutics in having a broader spectrum of activity. Thus there is the potential to tackle complex polymicrobial infections, with a single antimicrobial agent eradicating multiple microbes. This is an effi ciency that has provided an evolutionary advantage.

Ideal Drug Templates – But Not Ideal Drugs

For all the reasons detailed above, naturally derived antimicrobial peptides would appear to be obvious therapeutic candidates, and, in the past, efforts were made to employ endogenous peptides, fragments and closely related analogues for a number of infectious conditions (16). These attempts were largely unsuccessful however, because at that time, the highly complex and pleiotropic nature of natural antimicrobial peptide was not fully understood. Neither is it completely fully understood today, but we do now know that the antimicrobial functionality of these molecules only represents one of the multiple roles pleiotropic molecules play in innate immune defence. They are also proinfl ammatory factors, mitogenic agents and chemokines amongst other factors (11-15).

As mentioned previously, and as one would expect from molecules at the fi rst line of the body’s defence, endogenous antimicrobial peptides are produced (constitutively and in response to infectious challenge and infl ammation) at the interfaces between the body’s internal and external environment. As such, they are effectively mucosal factors (with the exception of neutrophilderived antimicrobial peptides – only released on degranulation with infl amed, infected or otherwise compromised tissue sites), that are never normally exposed to the systemic environment. It is not surprising therefore that with their pro-infl ammatory and haemolytic potential in mind (particularly for peptides comprising greater numbers of hydrophobic amino acids), analogues and fragments of endogenous antimicrobial peptides have been shown to have toxicity issues when administered systemically (15). In addition, antimicrobial peptides have complex secondary and tertiary structures, often with disulphide bridge linkers and are around 5kDa in size. They are therefore also challenging molecules to synthesise chemically as stable monomers.

A New Class of Antimicrobials

The key to unlocking the therapeutic potential of antimicrobial peptides is to determine the key components – sequence and structure – required for their antimicrobial functionality and from this, re-engineer simpler, smaller synthetic peptides that only retain the same if not enhanced antimicrobial capacity of their natural ‘relatives’, but which are truly druggable, not having the other ‘negative’ attributes of their endogenous counterparts, and that are readily synthesisable. Small, synthetic, novel cationic antimicrobial peptides designed on these principles have the potential for application across a range of topical and systemic infections as well as in coating a number of medically relevant devices (catheters, stents and so on).

Candidate Antimicrobial Peptide Therapies in Development

A number of companies have used this approach and have developed or are developing antimicrobial peptide drug candidates for a range of infectious indications (see Table 1). The fi rst in a next generation of peptide anti-infective agents will hopefully be approved for market from some of these programmes in the near future. Commercially Viable/Attractive Therapeutic Options Peptides have, in the past, had something of a bad reputation in terms of the negative connotations around costs of goods, product quality and scalability, stability and delivery. These factors are obviously key in the development of any drug candidate, and more recent progress in peptide chemistry and manufacturing techniques has meant that the costs of goods for peptide manufacture has reduced signifi cantly, with more options in terms of number of manufacturers.

A number of recent advances in peptide synthesis means that product quality, effi ciencies, costs and turnaround times are continuing to improve for peptide drugs and drug candidates. More than 95 per cent of pure peptides can be synthesised at tens, if not hundreds, of killogrammes per year. Hybrid synthesis strategies whereby longer and more complex peptides are produced by a combination of solid and solution phase syntheses, molecular hiving and other new technologies that facilitate efficient synthesis of large amounts of complex, and in some cases very long peptides possible, are adding even further to the attractiveness of antimicrobial therapies and dispelling previous negative assumptions of peptide production.

In regulatory terms, synthetic novel peptide structures are considered as a drug class that spans both the small molecule novel chemical entity and biologics drug families. Further regulatory clarity of late as to the most appropriate development path for peptide drugs has only helped the industry gain more confidence as to the scope for peptide anti-infectives in the future.

Conclusion

Peptide anti-infectives provide a much needed, novel therapeutic approach to combating bacterial, fungal and viral disease. Unlike the majority of their small molecule counterparts, peptide antiinfectives also show greater promise against drug-resistant microbes and emerging pathogens. Biotechnological innovation and rational drug-design based research approaches are driving development of this next generation of antimicrobials. Equally as important for their eventual introduction to clinical practice are recent advances in peptide synthesis and delivery technologies, reduced costs and improved quality in production. Furthermore, peptide therapeutics and biologics overall are gaining further regulatory acceptance with clearer development paths to the clinic being established as more gain approvals.

It is exciting to consider that peptide antimicrobials can provide a means to combating a spectrum of infectious diseases, not only in the short term until resistance development cuts short their usefulness – as it has for existing antibiotics (Figure 2) – but also for the longer term as resistance-free solutions to the continued, predicted future unmet clinical need for safer and more effective antimicrobials. We can look forward to the translation of this potential into clinical success, as the peptide anti-infectives currently in development progress through their drug development cycle as a stepchange in therapeutic options for a range of diseases.

References

  1. Spellberg B, Powers JH, Brass EP, Miller LG and Edwards JE Jr, Trends in antimicrobial drug development: implications for the future, Clinical Infectious Diseases 38(9): pp1,279-86, 2004
  2. Boucher HW, Challenges in antiinfective development in the era of bad bugs, no drugs: a regulatory perspective using the example of blood steam infection as an indication, Clinical Infectious Diseases 1(50) supplement pp1S4-9, Jan 2010
  3. Devasahayam G, Scheld WM and Hoffman PS, Newer antimicrobial drugs for a new century, Expert Opinion on Investigational Drugs 19(2): pp215-34, Feb 2010
  4. Clatworthy AE, Pierson E and Hung DT, Targeting virulence: a new paradigm for antimicrobial therapy, Nature Chemical Biology 3(9): pp541-548, 2007
  5. Bartlett JG, A call to arms: the imperative for antimicrobial stewardship, Clinical Infectious Diseases 53: supplement pp1:S4-7, Aug 2011
  6. MacPherson DW, Gushulak BD, Baine WB, Bala S, Gubbins PO, Holtom P and Segarra-Newnham M, Population mobility, globalisation and antimicrobial drug resistance, Emerging Infectious Diseases 15(11): pp1,727-32, 2009
  7. Türel O, Newer antifungal agents, Expert Review of Anti-infective Therapy 9(3): pp325-38, 2011
  8. The worldwide market for antiinfectives (antifungals, antibacterials and antivirals), Kalorama Reports Oct 1, 2009
  9. Anti-infectives: a global strategic business report, Global Industry Analysts Inc, 2010
  10. Butler MS and Cooper MA, Antibiotics in the clinical pipeline, The Journal of Antibiotics 64: pp413-425, 2011
  11. Hancock RE and Lehrer R, Cationic peptides: a new source of antibiotics, Trends in Biotechnology 16: pp82-88, 1998
  12. Gallo RL and Huttner KM, Antimicrobial peptides: an emerging concept in cutaneous biology, Journal of Investigative Dermatology 111: pp739-743, 1998
  13. Zasloff M, Antimicrobial peptides of multicellular organisms, Nature 415: pp389-395, 2002
  14. Ganz T, Defensins: antimicrobial peptides of innate immunity, Nature Review of Immunology 3: pp710-720, 2003
  15. Jerold GY and Romanowski EG, A review of antimicrobial peptides and their therapeutic potential as antiinfective drugs, Current Eye Research 30(7): pp505-515, 2005
  16. Pichereau C and Allary C, Therapeutic peptides under the spotlight, European Biopharmaceutical Review pp88- 91,Winter 2005

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Deborah O’Neil founded NovaBiotics Ltd in August, 2004. An immunologist by training with over a decade of experience in the field of natural antimicrobials, Deborah studied at University College London and then worked in internationally acclaimed laboratories in San Diego and Ghent before moving to Aberdeen. It was here where, in order to fully develop the commercial potential of novel antimicrobial peptide therapies, NovaBiotics was formed. Deborah has since grown the business to a leading global biotechnology company with clinicalstage compounds and a robust and exciting pipeline of anti-infective peptide drug candidates. Email: deborah@novabiotics.co.uk
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