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Naturally occurring antimicrobial cationic polypeptides play a major role in innate and adaptive immunity. These polypeptides are found to be either linear and unstructured or structured through disulfide bonds. Among the structured antimicrobial polypeptides, defensins comprise a family of cysteine-rich cationic polypeptides that contribute significantly to host defense against the invasion of microorganisms in animals, humans, insects and plants. Their wide-spread occurrence in various tissues of these diverse organisms, and their importance in innate and adaptive immunity have led to their identification, isolation and characterization. A large volume of literature is available on defensins' occurrence, structural characterization, gene expression and regulation under normal and pathological conditions. Much has also been published regarding their antimicrobial, antiviral and chemoattractive properties, and their molecular and cellular interactions. In this review, we describe the current status of our knowledge of defensins with respect to their molecular, cellular and structural biology, their role in host defense, future research paradigms and the possibility of their utilization as a new class of non-toxic antimicrobial agents and immuno-modulators.

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The solution structure of human salivary histatin 5 (D‐S‐H‐A‐K‐R‐H‐H‐G‐Y‐K‐R‐K‐F‐H‐E‐K‐H‐H‐S‐H‐R‐G‐Y) was examined in water (pH 3.8) and dimethyl sulfoxide solutions using 500 MHz homo‐ and heteronuclear two‐dimensional (2D) nmr. The resonance assignment of peptide backbone and side‐chain protons was accomplished by 2D total correlated spectroscopy and nuclear Overhauser effect (NOE) spectroscopy. The high J NH‐C αH values (≥7.4 Hz), absence of any characteristic NH‐NH(i, i + 1) or CαH‐CβH(i, i + 3) NOE connectivities, high dδ/dT values (≥0.004 ppm K−1) and the fast 1H/2H amide exchange suggest that histatin 5 molecules remain unstructured in aqueous solution at pH 3.8. In contrast, histatin 5 prefers largely α‐helical conformation in dimethyl sulfoxide solution as evident from the J NH‐C αH values (≤6.4 Hz), slow 1H/2H exchange, low dδ/dT values (≤0.003 ppm K−1) observed for amide resonances of residues 6–24, and the characteristic NH‐NH(i, i + 1) and CαH‐CβH(i, i +3) NOE connectivities. All backbone amide 15N‐1H connectivities fall within 6 ppm on the 15N scale in the 2D heteronuclear single quantum correlated spectrum, and the restrained structure calculations using DIANA suggest the prevalence of α‐helical conformations stabilized by 19 (5 → 1) intramolecular backbone amide hydrogen bonds in polar aprotic medium such as dimethyl sulfoxide. The interside‐chain hydrogen bonding and salt‐bridge type interactions that normally stabilize the helical structure of linear peptides in aqueous solutions are not observed. Histatin 5, unlike other naturally occurring antimicrobial polypeptides such as magainins, defensins, and tachyplesins, does not adopt amphiphilic structure, precluding its insertion into microbial membranes and formation of ion channels across membranes. Electrostatic (ionic type) and hydrogen bonding interactions of the positively charged and polar residues with the head groups of microbial membranes or with a membrane‐bound receptor could be the initial step involved in the mechanism of antimicrobial activity of histatins. © 1998 John Wiley & Sons, Inc. Biopoly 45: 51–67, 1998