Biotherapeutics

Research leader: Prof A Gaspar
Co-investigator: Prof A Neitz

Research focus

The research focus of the Biotherapeutics Research Group is the biochemical identification and characterisation of peptides/proteins from natural sources with therapeutic potential. Invertebrates, such as ticks, are rich sources of pharmacologically active agents. Most of the group’s previous research has been on tick anti-haemostatics. Tick defence molecules such as antimicrobial peptides (AMPs) and lipocalins, are good leads for the development of novel antibiotics. In search of novel anti-infective agents, the group is currently investigating the antimicrobial properties of shorter peptides based on a tick defensin. Besides their antimicrobial role, the tick derived peptides exhibit anti-endotoxin, anti-oxidant and nitric oxide scavenging activity. Multifunctional peptides may have further potential applications, for example in wound healing and as anti-sepsis agents. Understanding the structure-activity relationships of peptides with different bioactivities and their modes of action are necessary for the design of peptides with improved pharmaceutical efficacy.
Dietary proteins also provide a rich source of bioactive peptides which are released from food proteins during processing (enzymatically or fermentation) and during gastrointestinal digestion. Bioactive peptides present in indigenous fermented food products exhibiting antihypertensive, anti-oxidant and antimicrobial properties are currently being investigated. Bioavailability and mode of action studies of these peptides are essential to determine whether these products have any potential as health-promoting agents.

Background:

Anti-infective agents: A major concern in recent years is the growing number of microorganisms that have become resistant to conventional antibiotics [1]. Therefore, investigation into the development of new anti-infective agents has become increasingly important. AMPs which are key components of the innate immune system of multicellular organisms are promising candidates [2]. Besides being effective at low micromolar concentrations against a broad range of microorganisms, some AMPs possess antibiofilm activity [3]. In addition, AMPs participate in multiple aspects of immunity including stimulation of monocyte chemotaxis, inhibition of cytokine release and promotion of wound healing [4]. The long-term goal of this research project is to develop an anti-infective agent for the treatment of chronic wounds. Examples of chronic wounds include pressure sores, diabetic foot ulcers and wounds due to autoimmune disease [5]. These wounds may contain multiple biofilm-forming organisms (polymicrobial infections) [6]. Synthetic peptides with antimicrobial activity, antioxidant, anti-inflammatory and antibiofilm activities may promote rapid wound healing [6].
Bioactive peptides as health-promoting agents: Food-derived peptides have been shown to possess amongst others antihypertensive, anti-inflammatory, anti-oxidative and antimicrobial activities [7]. Bioactive peptides and peptide-rich hydrolysates thus hold potential for the prevention and treatment of human diseases [8]. Hypertension is a risk factor for cardiovascular disease including coronary heart disease, peripheral artery disease and stroke [9]. Angiotensin I-converting enzyme (ACE) catalyses the conversion of angiotensin I to angiotensin II (a vasoconstrictor), which subsequently increases blood pressure. In addition, ACE degrades bradykinin which has vasodilatory properties [10]. Antihypertensive peptides have shown activity both in vitro and in vivo and some have been incorporated into various food products [11]. Excessive inflammation and oxidative stress are associated with chronic diseases such as artherosclerosis and cancer. Although various food-derived peptides exhibit anti-inflammatory and anti-oxidant activity, research is still needed to determine their in vivo efficacy [8]. Interestingly, food-derived peptides also exhibit multiple functions. Antihypertensive peptides derived from plant-proteins were found to be possess antimicrobial activity [12].
References:
1. Levy SB (2002). Factors impacting on the problem of antibiotic resistance. J. Antimicrob. Chemother. 49: 25-30.
2. Zasloff M (2002). Antimicrobial peptides of multicellular organisms. Nature 415: 389-395.
3. Park S, Park Y & Hahm K (2011). The role of antimicrobial peptides in preventing multidrug-resistant bacteria infections and biofilm formation. Int. J. Mol. Sci. 12: 5971-5992.
4. Yeung ATY et al. (2011). Multifunctional cationic host defence peptides and their clinical applications. Cell. Mol. Life Sci. 68: 2161-2176.
5. Vasconcelos A & Cavaco-Paulo A (2011). Wound dressings for a proteolytic-rich environment. Appl. Microbiol. Biotechnol. 90: 445-460.
6. Duplantier AJ & Van Hoek ML (2013). The human cathelicidin antimicrobial peptide LL-37 as a potential treatment for polymicobial infected wounds. Front. Immunol. 4: 1-14.
7. Moller NP et al. (2008). Bioactive peptides and proteins from foods: indication for health effects. Eur. J. Nutr. 47, 171-182.
8. Chakrabarti S et al. (2014). Food-derived bioactive peptides on inflammation and oxidative stress. Biomed. Res. Int. 2014, Article ID 608979, http;/dx.doi.org/10.1155/2014/608979.
9. Keraney PM et al. (2005). Global burden of hypertension. Lancet 365, 217.
10. Brunner HR et al. (1972). Essential hypertension: renin and aldosterone, heart attack and stroke. N. Engl. J. Med. 286, 441-449.
11. Hernanzez-Ledesma B et al. (2011). Antihypertensive dpeptides: Production, bioavailability and incorporation into foods. Adv. Colloid Interface Sci. 165, 23.
12. McLean S, Beggs LB & Welch RW (2014). Antimicrobial activity of antihypertensive food-derived peptides and selected alanine analogues. Food Chem. 146, 443-447.