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S e p t e m b e r 0 6 - 0 7 , 2 0 1 8 | B a n g k o k , T h a i l a n d
Biotechnology Congress 2018 & Emerging Materials 2018
Note:
Page 19
allied
academies
EMERGING MATERIALS AND NANOTECHNOLOGY
BIOTECHNOLOGY
&
Annual Congress on
Global Congress on
Joint Event on
Biomedical Research
|
ISSN: 0976-1683
|
Volume 29
Fuad Fares, Biomed Res 2018, Volume 29 | DOI: 10.4066/biomedicalresearch-C4-009
NOVEL STRATEGY FOR DESIGNING
LONG-ACTING RECOMBINANT PROTEINS
FOR CLINICAL USE
O
nemajor issue regarding the clinical use ofmany peptides is their short half-
lifedue to the rapidclearance fromthecirculation.Toovercome thisproblem,
we succeeded to ligate the signal sequence of O-linked oligosaccharides
to the coding sequence of the hormones. The cassette gene that has been
used contains the sequence of the carboxyl-terminal peptide (CTP) of human
chorionic gonadotropin (hCG) subunit. The CTP contains 28 amino acids with
four O-linked oligosaccharide recognition sites. It was postulated that O-linked
oligosaccharides add flexibility, hydrophilicity and stability to the protein. On
the other hand, it was suggested that the four O-linked oligosaccharides play an
important role in preventing plasma clearance and thus increasing the half-life
of the protein in circulation. Using this strategy, we succeeded to ligate the CTP
to the coding sequence of follitropin (FSH), thyrotropin (TSH), erythropoietin
(EPO) growth hormone (GH) and thus to increase the longevity and bioactivity
of these proteins
in-vivo
. Interestingly, the new analogs of FSH and GH were
found not immunogenic in human and it is already passed successfully clinical
trials phase III and phase II respectively. Moreover, FSH long acting (ELONVA)
was approved by the European Commission (EC) for treatment of fertility
since 2010. In addition, our results indicated that long acting GH is not toxic
in monkeys and the results from clinical trials phase I and phase II seem to
be promising. Designing long acting peptides will diminish the cost of these
drugs and perhaps reduce the number of injections in the clinical protocols.
On the other hand, we found that deletion of N-linked oligosaccharides from
hTSH subunits resulted in significant decreased in the bioactivity. Moreover,
deglycosylated variants of TSH compete with normal hTSH and human
thyroid stimulating immunoglobulin (hTSI) in a dose dependent manner.
Thus, this variant, behaves as potential antagonist, who may offer a novel
therapeutic strategy in the treatment of Grave’s disease, the most common
form of hyperthyroidism. In conclusion, it was found that addition of O-linked
oligosaccharides or deletion of N-linked oligosaccharides could be interesting
strategy for designing new analogs of glycoprotein hormones.
Biography
Fuad Fares has completed his MSc and DSc stud-
ies at the Faculty of Medicine, Technion-Israel Insti-
tute of Technology, and postdoctoral studies at the
Department of Molecular Biology and Pharmacol-
ogy, School of Medicine, Washington University, St.
Louis Missouri. He developed the Department of
Molecular Genetics at Carmel Medical Center and
lead this department last 20 years. He is Associate
Professor at the Department of Human Biology,
University of Haifa and head the Laboratory of Mo-
lecular Genetics. He has published more than 90
manuscripts in reputed journals and served as a
Member of the Israel Council for Higher Education
last 15 years. He is the founder of PROLOR Biotech
company for designing long acting recombinant
proteins and CanCurX for identification of natural
products for treatment of cancer.
ffares@univ.haifa.ac.ilFuad Fares
University of Haifa, Israel