Antimicrobial peptides (AMPs) occur in all kingdoms of life and are integral to host defense. They have diverse structures and target a variety of organisms, both by nonspecific membrane interactions ...and via specific targets. Here we discuss the structures of AMPs from the four main classes currently recognized – that is, peptides with (i) α-helical, (ii) β-sheet, (iii) αβ, or (iv) non-αβ elements – as well as the growing pool of complex topologies including various post-translational modifications (PTMs). We propose to group these latter peptides into a fifth class of AMPs. Such peptides exhibit high stability and amenability to chemical engineering, making them of interest for the development of novel antimicrobial agents. Advances and challenges in the development of these peptides towards therapeutic leads are presented.
Antimicrobial peptides (AMPs) are ubiquitously expressed among all kingdoms of life and represent an integral part of an organism’s immunity.AMPs exhibit a wide range of classical structural motifs and are currently grouped into four categories based on the presence or absence of key structural elements such as α-helices, β-sheets, and various turns and loops.AMPs exhibit multiple modes of action, including interactions with biological membranes as well as activity at specific extra- and intracellular targets.Advances in peptide synthesis and structural characterization methodologies have increased our understanding of AMP structure–activity relationships and provide a means to tackle the current antibiotic crisis.Based on increasing reports of more complex structures such as disulfide-rich, cyclic, and lasso peptides as well as other post-translational modifications (PTMs), we propose to add a fifth structural group of AMPs accounting for these complex peptide topologies.
The Future of Peptide-based Drugs Craik, David J.; Fairlie, David P.; Liras, Spiros ...
Chemical biology & drug design,
January 2013, Volume:
81, Issue:
1
Journal Article
Peer reviewed
The suite of currently used drugs can be divided into two categories – traditional ‘small molecule’ drugs with typical molecular weights of <500 Da but with oral bioavailability, and much larger ...‘biologics’ typically >5000 Da that are not orally bioavailable and need to be delivered via injection. Due to their small size, conventional small molecule drugs may suffer from reduced target selectivity that often ultimately manifests in human side‐effects, whereas protein therapeutics tend to be exquisitely specific for their targets due to many more interactions with them, but this comes at a cost of low bioavailability, poor membrane permeability, and metabolic instability. The time has now come to reinvestigate new drug leads that fit between these two molecular weight extremes, with the goal of combining advantages of small molecules (cost, conformational restriction, membrane permeability, metabolic stability, oral bioavailability) with those of proteins (natural components, target specificity, high potency). This article uses selected examples of peptides to highlight the importance of peptide drugs, some potential new opportunities for their exploitation, and some difficult challenges ahead in this field.
Peptides fill a gap between traditional ‘small molecule’ drugs with molecular weights <500 Da and usually favorable oral bioavailability, and much larger ‘biologics’, typically >5000 Da, that are not orally bioavailable and need to be delivered via injection. Peptides in this size range are large enough to modulate protein:protein interactions, an increasingly important target class. Strategies to achieve the necessary stability and bioavailability of peptide drugs include the use of secondary structure mimics and stable cyclic peptide frameworks.
Cyclotides as drug design scaffolds Craik, David J; Du, Junqiao
Current opinion in chemical biology,
June 2017, 2017-Jun, 2017-06-00, 20170601, Volume:
38
Journal Article
Peer reviewed
•Cyclotides are ultra-stable and tolerant to sequence substitutions in all loops.•Sequences grafted into a cyclotide scaffold are stabilized and generally maintain biological activity.•Cyclotides can ...penetrate cells to deliver bioactive sequences to intracellular targets.•To date 26 studies of grafted cyclotides have been reported.•Applications include cancer, pain, cardiovascular disease, obesity and others.
Cyclotides are ultra-stable peptides derived from plants. They are around 30 amino acids in size and are characterized by their head-to-tail cyclic backbone and cystine knot. Their exceptional stability and tolerance to sequence substitutions has led to their use as frameworks in drug design. This article describes recent developments in this field, particularly developments over the last two years relating to the grafting of bioactive peptide sequences into the cyclic cystine knot framework of cyclotides to stabilize the sequences. Grafted cyclotides have now been developed that interact with protein or enzyme targets, both extracellular and intracellular, as well as with cell surface receptors and membranes.
Bioactive peptides have potential as drug leads, but turning them into drugs is a challenge because of their typically poor metabolic stability. Molecular grafting is one approach to stabilizing and ...constraining peptides and involves melding a bioactive peptide sequence onto a suitable molecular scaffold. This method has the benefit of improving the stability of the bioactive peptide lead and potentially expanding its functionality. Here we step through the molecular grafting process and describe its successes and limitations. So far, molecular grafting has been successfully used to improve the stability of peptide drug leads, to enhance conformational rigidity, to facilitate delivery to intracellular targets, and in some cases to increase efficacy in oral administration. Although applications of molecular grafting have focused mainly on therapeutic applications, including those for pain, metabolic disease, and cancer, its potential uses are much broader, and we hope this Perspective will inspire wider applications of this molecular design tool in biotechnology.
Cyclotides are plant-derived cyclic peptides that have a head-to-tail cyclic backbone and three conserved disulphide bonds that form a cyclic cystine knot motif. They occur in plants from the ...Violaceae, Rubiaceae, Cucurbitaceae, Fabaceae, and Solanaceae families, typically with 10–100 cyclotides in a given plant species, in a wide range of tissues, including flowers, leaves, stems, and roots. Some cyclotides are expressed in large amounts (up to 1 g kg−1 wet plant weight) and their natural function appears to be to protect plants from pests or pathogens. This article provides a brief overview of their discovery, distribution in plants, and applications. In particular, their exceptional stability has led to their use as peptide-based scaffolds in drug design applications. They also have potential as natural ‘ecofriendly’ insecticides, and as protein engineering frameworks.
Cyclotides: From Structure to Function de Veer, Simon J; Kan, Meng-Wei; Craik, David J
Chemical reviews,
12/2019, Volume:
119, Issue:
24
Journal Article
Peer reviewed
This Review explores the class of plant-derived macrocyclic peptides called cyclotides. We include an account of their discovery, characterization, and distribution in the plant kingdom as well as a ...detailed analysis of their sequences and structures, biosynthesis and chemical synthesis, biological functions, and applications. These macrocyclic peptides are around 30 amino acids in size and are characterized by their head-to-tail cyclic backbone and cystine knot motif, which render them to be exceptionally stable, with resistance to thermal or enzymatic degradation. Routes to their chemical synthesis have been developed over the past two decades, and this capability has facilitated a wide range of mutagenesis and structure–activity relationship studies. In turn, these studies have both led to an increased understanding of their mechanisms of action as well as facilitated a range of applications in agriculture and medicine, as ecofriendly crop protection agents, and as drug leads or scaffolds for pharmaceutical design. Our overall objective in this Review is to provide readers with a comprehensive overview of cyclotides that we hope will stimulate further work on this fascinating family of peptides.
From killers to curers: Peptides from cone snail venoms are potential therapeutic agents for the treatment of neuropathic pain. Unfortunately, these peptides suffer from the disadvantage of short ...biological half‐lives and poor activity when taken orally. A new orally active conotoxin was developed to solve these problems.
Seamless Proteins Tie up Their Loose Ends Craik, David J.
Science (American Association for the Advancement of Science),
03/2006, Volume:
311, Issue:
5767
Journal Article
Peer reviewed
Natural circular proteins found in bacteria, plants, and mammals show antimicrobial activity and exceptional stability, making them ideal templates for engineering better drugs. But just how they ...close into loops remains a mystery.
Disulfide bonds typically introduce conformational constraints into peptides and proteins, conferring improved biopharmaceutical properties and greater therapeutic potential. In our opinion, ...disulfide‐rich microdomains from proteins are potentially a rich and under‐explored source of drug leads. A survey of the UniProt protein database shows that these domains are widely distributed throughout the plant and animal kingdoms, with the EGF‐like domain being the most abundant of these domains. EGF‐like domains exhibit large diversity in their disulfide bond topologies and calcium binding modes, which we classify in detail here. We found that many EGF‐like domains are associated with disease phenotypes, and the interactions they mediate are potential therapeutic targets. Indeed, EGF‐based therapeutic leads have been identified, and we further propose that these domains can be optimized to expand their therapeutic potential using chemical design strategies. This Review highlights the potential of disulfide‐rich microdomains as future peptide therapeutics.
Disulfide‐rich microdomains are underexplored scaffolds for therapeutic drug design. In this Review, the most abundant domains present in the animal and plant kingdoms are highlighted, and their structures and functional activities are analysed to provide an insight into their use in design of next‐generation peptide therapeutics.
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