The Advent of Recombinant Peptides [Peptide Drug Discovery – Part 2]

In the last issue, we had an in-depth discussion about the emergence and rise of peptide therapeutics. So far, we have been knowledgeable about the introduction of insulin, the burdens of the early days in peptide research, and the massive return of peptide drugs in the mainstream. In continuation to the previous article of the peptide therapeutics series herein we shall discuss the further developments, the introduction to the recombinant peptides.

Article published in last issue: The Rise of Peptide Therapeutics

What is recombinant technology?

The Advent of Recombinant Peptides - recombinant technology

It’s a kind of engineering on the natural molecules. The term “recombinant” is mostly used for “Recombinant DNA”, which are actually the modified DNAs derived in the laboratory by performing genetic engineering on the mother DNA.

In a similar way, when scientists find a natural peptide that exhibits some sort of biological potentiality with certain restrictions, they think to apply specific modifications to it.

These modifications may be performed multiple may, such as altering certain amino acids in the peptide chain, the introduction of natural or unnatural amino acid within the mother peptide, methylation on the free amine groups, converting a long-chained peptide to a cyclic peptide, or even inserting small heterocycle in the peptide.

So far massive research on recombinant technology has been performed to increase the efficiency of natural peptides, and several peptide drugs have been approved by following this method.

The Advent of Recombinant Peptides

The advent of recombinant technology in peptide drug discovery is a milestone that provides a reliable and facile alternative to synthetic peptides. This technology certainly accelerated peptide research as well as the approvals of peptide-based drugs.

Owing to the initiation of allergic reactions, pig- or cow-derived Insulin was not ideal for medicinal utility. Scientists invested restless effort to obtain a better result and finally, Genentech and Eli Lilly developed a complex heterodimer of insulin having 21 amino acid residues in chain A, 30 amino acid residue in chain B, and three disulfide bonds (for molecular diagram see previous part HERE). The drug was approved in 1982.

Notably, Somatostatin was known to be the first recombinantly derived human peptide as described in the earlier part of the Peptide Therapeutics series.

Introduction of genetic engineering in peptide drug discovery

The advent of recombinant technology reached the next level when genetic engineering was permitted to modulate the absorption, distribution, metabolism, and excretion.

Theoretically, when peptide therapeutics are applied in the body, slow but long-term effects are required to obtain the best results. That means a peptide needs to stay in active form for up to 1-6 months in the body so that it can act slowly in a continuous way to cure or control the disease.

However, it was observed that pure insulin forms inactive hexamers upon long-term storage in the body. Eventually, it becomes useless, and hence frequent doses required for controlling its target disease.

By applying genetic engineering strategy, several fast-acting and slow-release insulin analogs could be prepared, which remarkably improved the efficiency of insulin, and soon later it captured a multi-million dollar market.

Recombinant Peptides that control Calcium concentration in blood

In 1961, Calcitonin (a 32 residue peptide) was extracted from the thyroid-like gland of salmon which could effectively lower the blood calcium levels in dogs. Later, its high potential to inhibit bone resorption was also uncovered. In 1978 a synthetic version of Calcitonin was derived, and in the same year, it was approved for the treatment of hypercalcemia and postmenopausal osteoporosis.

Recombinant Peptides - Calcitonin
Calcitonin – AA residue sequence

After several years, in 2005, the recombinant version of Calcitonin was approved that exhibited better selectivity and higher potentiality.

Parathyroid hormone or PTH (84 residue peptide) was first discovered in 1925 and found to increase the calcium levels in the blood, acting exactly opposite to the role of Calcitonin. It can release calcium from the reservoirs in bones by triggering PTH 1 and PTH 2 receptors. However, it was observed that long-term storage of PTH could result in the depletion of bone stores by randomly activating the osteoblasts.

Recombinant Peptides - parathyroid hormone
Parathyroid hormone – AA residue sequence

After years of research, teriparatide was derived via recombinant technology by considering only the bioactive portion of the human PTH (34 residues). In 2002, teriparatide was approved for the treatment of osteoporosis and known to be the first agent that could treat osteoporosis bone-forming mechanism.

Very recently, in 2017 abaloparatide was approved for the improved treatment of osteoporosis, (this is a synthetic analog of PTH-related protein (PTHrP)).

In 2015, a full-length PTH therapy was approved to control the low calcium concentration in blood in hypoparathyroidism patients.

More Recombinant Peptides Approved as Therapeutics

Recombinant technology allowed the derivation of versatile peptide analogous that enhanced the approval rate of new peptide drugs. See the complete list below:

Insulin varieties for Type 1 & 2 Diabetes

Generic nameAA ResidueBrand nameCompanyTreatmentYear of Approval
Insulin (human)51Humulin, Novolin, Afrezza  Eli Lilly, Novo Nordisk, Chiron, Zymo, Genentech, Wockhardt, Hoechst, Organon, Biobra, Mannkind  Type 1 and 2 diabetes1982
Insulin mixtures  51Humalog Mix 50/50 and 75/25, Humulin 50/50, 70/30, NovoLog Mix 50/50, 70/30, Novolin 70/30, Ryzodeg 70/30, Xultophy  Novo Nordisk, Eli LillyType 1 and 2 diabetes1989
Insulin lispro51Humalog, Humalog Kwikpen, Humalog Pen  Eli Lilly Type1 and 2 diabetes1996
Insulin aspart51NovologNovo NordiskType 1 and 2 diabetes2000
Insulin glargine  53Lantus, Basaglar, Toujeo Solostar  Sanofi Aventis, Eli LillyType 1 and 2 diabetes2000
Insulin glulisine  51Apidra, Apridra Solostar  Sanofi AventisType 1 and 2 diabetes2004
Insulin detemir50LevemirNovo NordiskType 1 and 2 diabetes2005
Insulin degludec50TresibaNovo NordiskType 1 and 2 diabetes2015

Specific drugs for type 2 diabetis

Generic nameAmino Acid ResidueBrand nameCompanyTreatmentYear of Approval
Liraglutide37Victoza, SaxendaNovo NordiskType 2 diabetes, obesity2010
Albiglutide xx2×30Tanzeum, EperzanGlaxoSmithKlineType 2 diabetes2014
Dulaglutide2×30TrulicityEli Lilly and CoType 2 diabetes2014
Semaglutide31OzempicNovo NordiskType 2 diabetes, obesity2017
 31Rybelsus (oral formulation)  Novo NordiskType 2 diabetes 2019

Calcium concentration controlling peptide therapeutics

Generic nameAA ResidueBrand nameCompanyTreatmentYear of Approval
Calcitonin (salmon)32Acticalcin, Forcaltonin, Fortical,  TRB Pharma, UnigenePostmenopausal osteoporosis2005
Teriparatide, rhPTH (1-34)  34Forteo, ForsteoEli LillyOsteoporosis2002
Parathyroid hormone  84NATPARANPS Pharms Inc.Control hypocalcaemia in patients with hypoparathyroidism  2015

Heart disease-related drugs

Generic nameAA ResidueBrand nameCompanyTreatementYear of Approval
Carperitide, NPPA protein, human alpha-atrial natriuretic peptide, hANP28HANP injection 1000Daiichi PharmaceuticalAcute heart failure1995
Nesiritide, hBNP xx32NatrecorSciosCongestive heart failure2001

Miscellaneous recombinant peptide therapeutics

Generic nameAA ResidueBrand nameCompanyTreatmentYear of Approval
Glucagon28GlucaGen, GlucagonNova Nordisk, Eli Lilly, ZymoGenetics  Severe hypoglycemia, antihypoglycemic agent, gastrointestinal motility inhibitor1998
Teduglutide36Gattex, RevestiveNycomedShort bowel syndrome2012
Mecasermin70IncrelexIpsenInsulin-like growth factor 1 deficiency2005

The expansion of the genetic code and the combination of genetic code expansion with display technologies are the area of major interest nowadays for deriving more effective peptides and proteins. The incorporation of unnatural amino acids, N-methylated amino acids, β-amino acids, d-amino acids, and thioamides in the existing peptide, and derivation of cyclic peptides are showing promising results in the peptide drug discovery field. Undoubtfully, the recombinant technology is successfully uplifting the peptide research to the next level.

[Continue to the next issue]

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Dr. Suvankar Das pursued his doctoral degree in Chemistry in 2015. Further, he was associated as postdoctoral researcher (Synthetic & Medicinal Chemistry) and research scientist in several institutes and companies. Presently he is associated with multiple organizations as an editorial board member and scientific consultant.

With the aim to deliver updated information about novel discoveries and unknown facts of science, Dr. Suvankar Das founded SynnBiob Science Magazine. He believes, exploring sustainable science in a divergent way is the ultimate path to create a beautiful world.

Besides his scientific journey, he is also a passionate traveler. Travel Entice (https://travelentice.com), which is his other foundation, gained immense popularity recently.

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