**1. Introduction**

Found in virtually all organisms, antimicrobial peptides (AMPs) are short, positively-charged oligopeptides that exhibit a diversity of structures and functions. AMPs are a fundamental component of the innate immune system and play a vital role in the initial immune response generated against both injury and infections. AMP-mediated immune responses are rapidly activated following infections as AMPs are primarily synthesized and stored in cells of myeloid origin and epithelial cells, among the first responders to infections. AMPs are expressed in a wide variety of tissues including skin, eyes, oral cavity, ears, airway, lung, female reproductive tract, cervical-vaginal fluid, intestines, and urinary tract [1,2]. The majority of AMPs are synthesized as large polyprotein precursors, the proteolytic processing of which releases active peptide segments which can be present alone or in multiple copies. Removal of signal peptide may be a post-translation or a co-translational process. Processed functional peptides have been characterized into many classes in mammals; in humans, they include defensins, cathelicidins, transferrins, hepcidin, human antimicrobial proteins, dermcidin, histones, AMPs derived from known proteins, chemokines, and AMPs from immune cells, antimicrobial neuropeptides, and Beta-amyloid peptides [3]. While all of the AMPs classes have been shown to possess antimicrobial activity, only a few classes have demonstrated antiviral properties.

A defining feature of AMPs is their rapid response to infections of bacteria, viruses, fungi, or protozoa [1,4]. Exhibiting inhibitory and immunomodulatory properties, AMPs have been intensively studied as alternatives to antibiotics in bacterial infections and in recent years have gained substantial

attention as viral therapeutics [5]. Here we report on the application of human AMPs in the treatment of viral infections.

#### **2. Defensins**

#### *2.1. Expression*

Highly abundant and widely distributed, defensins modulate immune responses thereby playing a central role in innate immunity [6–8]. Defensins are classified into three subgroups: α, β and θ. Although humans do not produce functional members of the θ-defensin family of AMPs, expression of θ-defensin mRNA has been observed in humans. The θ-defensin mRNA contains a pre-mature stop codon which prevents translation; however, functional θ-defensins are present in non-human primates [9]. To date, six α-defensin and 31 β-defensin peptides have been identified in various species [9]. Originally isolated from neutrophils, four of the six distinct α-defensins are termed human neutrophil peptides (HNP-1 through 4). They are also produced by myeloid-lineage cells such as macrophages, natural killer (NK) cells and some classes of T and B-cells. α-defensins 5 (HD5) and 6 (HD6) are expressed in epithelial cells in the small intestine [6,8–10]. The β-defensin family of AMPs is commonly expressed in birds and mammals. In humans, three β-defensins (HBD-1 through 3) have been fully characterized and a fourth, HBD-4, was recently identified. β-defensins are primarily expressed by epithelial cells and keratinocytes, but can also be produced by neutrophils, macrophages, mast cells, NK cells, dendritic cells, and lymphocytes [6–8,10]. Current data suggest a functional redundancy when comparing the efficacy of α and β defensins against various pathogens [11].

Defensins are defined by the presence of a conserved spacing pattern comprised of cysteine residues, which is critical for the efficacy of their cationic antimicrobial properties [9,12]. Human α-defensins are composed of 29 to 34 amino acids with an overall positive charge [9,12,13]. Defensins exhibit a characteristic β-sheet structure with a distinctive six-cysteine motif for which stabilization is a consequence of the presence of three intramolecular disulfide bonds. The α-defensins are synthesized as pre-propeptides consisting of a N-terminal signal sequence, an anionic pro-peptide, and a C-terminal mature peptide comprised of approximately 30 amino acids. HNP1, HNP2, and HNP3 are synthesized by promyelocytes and stored in primary neutrophil granules as mature peptides [10]. In contrast, β-defensins have a short N-terminal pro-region and can retain antimicrobial activity in full-length form, and; therefore, do not require N-terminal processing to be fully active [14]. They are synthesized in epithelial compartments and can range from 38 to 42 amino acids in length.
