the term “ substantial homology ” as used herein is intended to mean sequences of amino acids which have at least 60 % and preferably at least 80 % identity of unit and sequence with the natural product histatin h - 5 . it has been found that there is considerable tolerance of substitution of individual amino acids in histatins , without substantial loss of activity . histatins h - 5 8 - 24 , h - 5 and h - 3 and analogs and mutations thereof an be prepared by standard methods of peptide synthesis . the analogs may comprise d - amino acid analogs , l - amino acid analogs , and analogs incorporating random or preselected mixtures of d - and l - amino acids , in the predetermined , defined sequence . chemical syntheses for step - by - step assembly of peptides using predetermined sequences of amino acid starting units , with appropriate chemical protection and deprotection steps , are well known and can be adopted in preparation of analogs according to the present invention . preferred syntheses use solid phase peptide synthesis technology , e . g using 4 - alkoxybenzyl alcohol or 2 - chlorotrityl chloride solid support resins , on a continuous flow synthesizer . they can also be prepared by the batch mode method as originally described by merrifield . the peptides can also be made by solution methods or by a combination of liquid phase and solid phase methods . the n - amino group of the amino acid is suitably protected with a base labile fluorenylmethoxycarbonyl ( fmoc ) group or a t - butyloxycarbonyl ( boc ) group during synthesis while its acid group is reacted . tyrosine , serine , threonine , glutamic acid and aspartic acid side groups are suitably protected with t - butl groups during chain extension . potential racemization of the imidazole ring of histidine is suitably blocked by use of an n - trityl group . the reactivity of cysteine side chains can also be masked with a trtyl group . arginine residues are appropriately protected at their n - terminus with pentamethylchroman - 6 - sulfonyl ( pmc ) groups . lysine is suitably protected with boc groups . coupling of amino acids is suitably achieved by activating the first amino acid with benzotriazol - 1 - yloxytris ( dimethylamino ) phosphonium hexafluorophosphate ( bop ) and 1 - hydroxybenzotriazole , to form the active ester . activators such as n - methylmorpholine ( nmm ) or collidine may also be used to assist in the reaction . other common coupling agents such as dcc , hbtu , hatu etc can be used . all these peptide synthesis techniques , and equivalents and alternatives to them , are within the skill of the art and well known to skilled peptide chemists . the peptides so formed may be cleaved from their solid synthesis supports by standard protocol using trifluoroacetic acid and appropriate scavengers , and the blocking groups by standard procedures . the peptides so formed can be purified by reverse phase hplc . peptides containing only l - amino acids can be obtained by chemical synthesis or by dna recombinant techniques . other peptides with d - amino acids or with lactam groups as the means for providing cyclization are prepared by chemical synthesis or by semi - synthesis using enzymes . the synthetic protocol ( couplings , deprotection and cleavage times ) may be optimized for a continuous flow synthesizer ( millipore 9050 ) using fmoc - chemistry . electrospray mass spectrometer ( esms ) is used to detect deletions and other side reactions . purification to homogeneity is achieved by reverse phase hplc using a c - 18 column . in general , overall yields of pure peptides are greater than 60 % ( as high as 90 %) and quantities & gt ; 100 mg are routinely obtained . to prepare the cyclic peptides of the present invention , it is necessary to make at least one amino acid substitution , as compared with histatin h - 5 . the natural product contains within the region forming the active loop structure lysine groups , which in one embodiment of the invention can be used as points of cyclization , utilizing their free amino groups in reaction with free carboxyl of glutamic acid to form a lactam ( amide ) link and result in ring formation . however , the glutamic acid residue naturally present in histatin h - 5 , at position 16 , should preferably be left intact and not utilized in the cyclization , since it appears to have a role in the activty of the final compounds . accordingly , it is preferred to introduce a glutamic acid as a substitute amino acid group for purposes of reaction with lysine to form the cyclized form , via a lactam group . lysine , for participation in the cyclization reaction , can also be introduced as a substitute group , or alternatively one can make use of one of the lysine groups naturally present . an alternative and preferred amino acid substitution into the histatin analogs for cyclization purposes in the present invention is cysteine , which can readily be introduced by known methods , in place of any of the naturally occurring amino acids of histatin . cysteine residues in the peptide chain readily form disulfide bridges between themselves so as to impart the necessary cyclic structures . while the bonds are chemically reversible , they are sufficiently permanent to meet the criteria for compounds of the present invention . as alternatives to cysteine , there can be used other thiol - containing amino acids e . g . homocysteine or penicillamine . bicyclic analogues with two disulfide bridges or one disulfide and one lactam bond can also be made . head - to - tail cyclization can also be made . cyclization can also be done by other chemical means , e . g . by thioether linkage . peptides containing cysteine substitutions and cyclized through disulfide groups can be made by air oxidation of the free linear peptide in a 0 . 1 molar solution of ammonium bicarbonate , with selective protection of the cysteine . lactam - cyclized peptides can be prepared by the selective removal of the aloc / allyl lys and glu side chain protecting groups under mild conditions with a pd ( 0 ) catalyst while the peptide is still attached to the resin and the other side chains remain protected . an amide bond can then be formed between the side chains using ( benzotriazolyloxy ) tris ( dimethylamino ) phosphonium hexafluorophosphate ( pybop0 and hobt as coupling reagents , or with other common coupling reagents . then the cyclized peptide can be cleaved from the resin and purified by reverse phase hplc . potential applications in health care industry include orally administrable formulations ( tablets , capsules , lozenges , chewing gums , etc , with standard , known fillers , extenders , excipients and the like ), tooth paste , mouth wash products , other dental care products , antiperspirant , coatings on protective device for wound dressing ( e . g . bandaid ®). other potential medical applications in medicine include wound healing and tissue regeneration after surgery or accidental trauma . using the standard techniques of peptide synthetic chemistry described above , a series of histatin h - 5 analogs according to the present invention was prepared , the amino acid sequences of which are listed below in table 1 , along with that of the naturally occurring h - 5 . each possessed substantial homology with h - 5 from position 5 to position 19 of the natural h - 5 , and in some cases beyond . each contained two cysteine groups c in replacement of two naturally occurring amino acids of h - 5 , from 5 to 14 amino acids apart , and cyclized as described above to insert disulfide bridges between the two cysteine groups c and create cyclic peptide structures having loops or rings from 7 to 16 amino acids in length . in some cases , e . g . db2 - 121 , additional deletions were made so that the amino acid chain was shorter than that of either of h - 5 or h - 3 . in some cases also , additional substitutions were made , but leaving the product within the range of substantial homology with h - 5 . the compounds of table 1 were tested for fungistatic activity with an assay based on the work of gordon , lapa et . al . ( 18 ) with the nonpathogenic yeast s . cerevisiae in which ketoconazole is used as control . a semisolid is prepared to which is added serial dilutions of peptide . this antifungal agar is distributed in a well plate , and the s . cerevisiae inoculum is then added to each well . both ketokonoazole and h - 5 are used as positive controls and buffer is used as a control blank . minimum inhibitory concentration mic , i . e . the concentration of the peptide under test which prevents growth , as observed visually , is recorded for each sample so that low values of mic indicate potent antifungal compounds . more specifically , stock peptide solutions ( 600 microliters or 1 ml ) were prepared to 10 times the final concentration of the most concentrated test sample in a sodium phosphate buffer ( 0 . 01 m0 , ph 7 . 4 ). peptide concentrations were determined by uv absorbance at λ = 275 . control blanks were also prepared using 1 ml buffer five serial dilutions were made in sterile culture tubes with buffer to create a range of peptide concentrations . the final volume in each tube was either 300 microliter or 1 ml . agar medium ( 2 . 7 or 4 . 5 ml ) was added to each tube and mixed . aliquots ( 1 ml ) of each were added to a 24 well plate to give 6 different concentrations of each peptide per plate . each plate had a row of control blanks and a row of a positive control ( ketoconazole ). a stock solution ( 10 mg / ml dmso ) was diluted 1 : 49 with buffer . a range of final concentrations of 20 to 0 . 16 micrograms / ml was tested . in addition , in later analog assays , h - 5 was included as a positive peptide control . histatin 5 was tested in a range from 200 micromolar to 6 . 3 micromolar . other analogs were tested at concentrations anywhere from 200 μm down to 0 . 14 μm ubtil the analog with lowest mic concentration was identified . s . cerevisiae cells grown overnight were centrifuged and washed with a 0 . 85 % saline solution , three times . cell concentration was adjusted to 85 % transmission at λ = 530 with saline solution . cells were further diluted 1 : 19 . inoculant ( 10 microl ) was added to the peptide - containing medium . the cells were incubated on this medium for 24 hours at 37 ° c . the fungistatic mic for these compounds was defined as the minimum concentration required to achieve 100 % inhibition after 24 hours . substantial improvement of activity can be obtained . db2 - 121 ( gly 9 −& gt ; cys , ser 20 −& gt ; cys ) was found to be most potent with a mic of 0 . 3 μm which is approximately 100 times more potent than h - 5 and 10 times more potent than ketoconazole against s . cerevisiae . importantly , a similar activity profile for db2 - 121 is observed against c . albicans and against three different bacteria ; is . aureus ( gr +). e . coli ( gr −) and β . magatenum ( gr +). from studies of the cysteine scan , it is quite evident that loop stabilization by correct disulfide cyclization is one way to enhance the activity of h - 5 and related peptides . db2 - 121 is 19 amino acids long and therefore shorter than h - 5 or h - 3 . additional deletions at the c - terminal ( db2 - 19 and db2 - 15 ) can be done but with small loss of activity . a disulfide containing peptide with d - amino acids at each end of the chain was prepared and evaluated for biological activty — compound db3 - 35 . this type of modification often increases the stability of peptides towards proteolytic degradation . as often seen with other peptides , loop stabilization may also increase the proteolytic stability . a hypotonic assay based on the work of helmerhorst et . al ( 19 ) was used to determine the loss of cell viability of c . albicans in the presence of peptide compounds of the present invention . this protocol involves incubating the peptide and cells in a low osmolality solution for 1 , 5 hours with constant mixing . standard plate count procedure is then followed to determine the concentration of viable cells remaining . by determining the cell concentration levels in negative control wells , the % loss of cell viability due to the presence of the peptide is determined . mics for h - 5 and h - 5 8 - 24 were similar to those reported against c . albicans . preliminary toxicity studies indicate that at least one of the cyclic analogs tested has no acute toxicity in mice ( 5 mice ) after injection of a rather massive dose ( 15 mg / kg ) in the intraperitoneal cavity . we also synthesized db2 - 100 , a peptide which contains two disulfide bonds ( giving a bicyclic peptide ), by selective protection of the cysteine . in this preparation , the first set of protecting groups , the trityl groups , were removed and oxidized as described above . the second set of protecting groups , the acetamidomethyl ( acm ), were removed with iodine , and the resulting peptide purified by rp hplc and air oxidized to form the second disulfide bridge . the bicyclic structure is even more conformationally constrained that the other analogs and the compound has retained its biological activity — mic range determined as described for the compunds of example 1 is 0 . 63 - 1 . 25 . to demonstrate that the cyclic structure of the peptide , and not the presence of the disulfide itself , is determinant for optimal activity , we prepared db3 - 41 a peptide analog of db2 - 121 in which the cyclization is effected by means of an amide bond ( lactam ) between the side chain of a glutamic acid and lysine , by methods described above . the glutamic acid is at position 9 and lysine at position 20 . in this case , where an orthogonal protection scheme was required , the allyloxycarbonyl ( aloc ) protecting group was used for lysine , and the allyl group was used for glutamic acid . the full sequence of db3 - 41 is arg his his lys tyr arg lys phe his glu lys his his glu his arg gly tyr . ( seq id no : 27 ) the fungistatic activity of db3 - 41 is comparable to db2 - 121 , i . e . mic range ( μm ) 0 . 55 - 1 . 1 . 1 . s . e . blondelle , r . a . houghten , annuals reports in medicinal chemistry ( 1992 ), 27 159 . 2 . f . g . oppenheim et al . j . biol . chem . ( 1986 ) 261 1177 . 3 . f . g . oppenheim et al . j . biol . chem . ( 1988 ) 263 7472 . 4 . r . f . troxler , f . g . oppenheim et al . j . dent . res . ( 1990 ) 1 2 . 5 . j . c . vanerspek et al . arch . oral biol . ( 1990 ) 35 137 . 6 . c . f . richardson et al . arch . oral biol . ( 1993 ) 38 997 . 11 . b . j . mackay et al . infect . immun . ( 1984 ) 44 695 . 14 . p . a . raj et al . j . biol . chem . ( 1990 ) 265 3898 . 15 . p . a . raj et al . j . biol . chem . ( 1994 ) 289 9610 . 16 . y . zuo . f . g . oppenheim et al . gene ( 1995 ) 161 87 . 18 . m . gordon et al ., j . clinical microbiol . ( 1988 ) 26 1874 . 19 . e . j . helmerhorst et al ., j . biol . chem . ( 1999 ) 274 7286 .