Biopharmaceutical firm Oragenics has received funding from a US government agency for a technology which promises cost-effective production of commercially important bioactive peptides with unusual structures.
The Small Business Innovation Research (SBIR) Phase 1 grant from the National Science Foundation (NSF) will allow Oragenics to test its Differentially Protected Orthogonal Lanthionine Technology (DPOLT) by synthesising nisin, a lantibiotic that has been used as a food preservative but which no one has been able to purify.
Lantibiotics, such as Oragenics' lead antibiotic MU1140, are a family of polycyclic peptides that are produced by bacteria and are highly modified structurally, however, attempts to study them as therapeutic agents have been hindered by difficulties in producing sufficiently pure material in amounts adequate for the required preclinical testing.
Unfortunately, the common method for synthesising peptides, solid phase peptide synthesis (SPPS), despite its speed and efficiency, has limitations in the production of complex protein strucutres, such as the intertwined rings found in many lantibiotics.
There are curently at least 25 reported lantibiotics that have an intertwining ring structure but no one has been able to find fermentation methods for cost effective production and/or purification.
Nevertheless, through the chemical synthesis of two unusual amino acids, DPOLT can be integrated in routine SPPS to synthesize lantibiotics in a rapid, pure, and cheap manner.
These two unusual amino acids can be prepared in bulk and are therefore cheap to make.
Thus, DPOLT allows to rapidly synthesise and screen the known lantibiotics to identify the ones that are best suited for further development, and could potentially be used for large-scale manufacturing.
"The methods are scalable and the costs should be quite reasonable as compared to 'regular' amino acids currently used in routine SPPS," Jeff Hillman, chief scientific officer of Oragenics, told In-PharmaTechnologist.com.
"As far as SPPS itself is concerned, there are a number of bioactive peptides already on the market that are made using this approach, indicating that it is a cost-effective format."
In SPPS, the first carboxyl terminal amino acid is attached to a resin and a protecting group is removed from its amino group, the resin is then collected and washed to remove any unreacted substrate and the second amino acid is attached to the amino group of the first amino acid, with the washing steps and addition steps repeated until the entire peptide has been built.
DPOLT uses two unusual amino acids in SPPS with carefully selected protecting groups on their reactive carboxyl and amino groups, which can be differentially removed as needed.
Apart from DPOLT, there are no other methods currently available for the manufacture of lantibiotics.
Oragenics will spend the next six months performing a proof of principle by synthesising nisin and once this is successfully completed, they will begin to manufacture lantibiotics for testing.
The testing may be carried out by Oragenics or the molecules could be licensed to companies interested in new antibiotics.
There are also a number of other bioactive molecules that have disulfide bridges, which may be improved using DPOLT since it will substitute thioether bridges for the disulfide bridges making them more stable in vivo.
The company, which has filed a US patent application covering the intellectual property surrounding the DPOLT-SPPS technology, expects commercialisation to begin within a year.