Peptide therapeutics target dynamic protein-to-protein interaction underlying human diseases such as hypertension, cancer, Alzheimer’s disease and potentially COVID-19

Increasingly, peptide-based drugs are finding utility in medicine.  This is not surprising given that many of the physiological processes are carried out by endogenously expressed peptides, ex. hormones, neurotransmitters, naturally occurring antibiotic molecules, etc.—with insulin being one of the earliest peptide drugs.  With ~60 peptide drugs having been approved in the U. S. and ~20 new peptide drugs entering clinical trial yearly (~400 peptide-based drugs are being tested globally), it has become a leading pharmaceutical industry (Lee et al., 2019).

For pharmacological application, peptides present multiple advantages.  Peptides are less toxic as they can be biologically degraded. Unlike chemical drugs, they do not accumulate in body.  Peptides are less immunogenic and can penetrate tissue (ex. tumor) more efficiently than antibodies.  Further, peptide can be engineered to translocate across the cell membrane to reach intracellular targets, which most monoclonal antibodies cannot.  As a result, pharmaceutical industries have devoted major efforts to improve its pharmacodynamic and pharmacokinetic properties by increasing its stability in vivo, reducing its clearance by the kidney, etc. (Davenport et al., 2020).

Within cells, many of the biological processes require protein-to-protein interaction.  Examples include filaments polymerized from monomers, enzymes assembled from subunits, DNA repair complexes comprised of multiple distinct proteins, receptors interacting with associating proteins for cell signaling, etc.  Of great significance is the ability of peptides to bind to large, extensive and flat interfaces, which offers unique pharmacological opportunities.  It provided a major advantage over chemical drugs that have been used primarily to target well defined pockets formed through protein folding.

There has been a paradigm shift in how the receptor-ligand interactions are portrayed.  The conventional, static view is being replaced by a fluid model as receptors were shown to adopt multiple conformations in vivo.   This has also impacted peptide drugs.  The classic view portrayed them as mere agonist or antagonist, taking into account of both the binding affinity and the effect on the function of the receptor.  An emerging view may incorporate its interaction with multiple key positions within the binding domain of the receptor occurring in a dynamic manner (Lee et al., 2019).


A significant portion (>40%) of peptide drugs target G protein-coupled receptors (GPCR).  GPCRs are seven-transmembrane domain receptors present on cell surface and respond to external stimulus such as odor, light, hormones, neurotransmitters, etc.  Upon binding to a ligand, it undergoes conformational change to activate the associating protein (G protein) to exchange GDP for GTP, resulting in the dissociation of the latter’s alpha subunit to initiate intracellular signaling.  GPCRs are involved in diverse physiological functions including inflammation, behavior, vision, etc. and its dysfunction leads to various human diseases including asthma, high blood pressure, cancer, obesity, mental illness, infectious diseases and others.  Additionally, peptide drugs have targeted transcriptional complexes regulating the genes involved in cell proliferation (i.e. oncogenesis) or cell differentiation (Inamoto et al., 2017).   Peptides can be used as therapeutic or for drug delivery.  In 2018, the largest segment (>37%) of its application was for cancer and the market is projected to increase to USD 51 billion by the year 2026.

With the recent COVID-19 pandemic, molecular targeting has picked up pace to find suitable therapeutics to counter the coronavirus.  Greater than 20 peptide drugs are in pipeline to treat COVID-19—among them, 15 synthetic peptides are being developed to treat Acute Respiratory Distress Syndrome (ARDS) and other respiratory illnesses resulting from COVID-19 infection.  Through computer simulation, the investigators at the Massachusetts Institute of Technology (USA) have synthesized peptide derivatives corresponding to an alpha helix of ACE2 that interacts with the spike protein (S) of COVID-19 to block infection (Zhang et al., 2020).  Another group developed peptide inhibitors formed by 2 sequential self-supporting alpha helices of ACE2 to bind to S protein (Han et al. 2020).  As an alternative strategy, other researchers employed supercomputers (Texas Advanced Computing Center) to simulate biomolecular environment to refine the chemical structure of candidate peptide drugs to inhibit “main protease” necessary for the propagation of COVID-19.  To treat lung injury, a number of synthetic peptide drugs are being repurposed for COVID-19 clinical trials such as Solnatide to treat alveolar edema, Plitidepsin originally developed to treat cancer (multiple myeloma), etc.  For vaccine development, peptide libraries have been developed consisting of peptides derived from COVID-19 polypeptides to facilitate B-cell or CTL (cytotoxic T cell) epitope mapping.

The key to preventing epidemic is the ability to diagnose the infected early to preempt further propagation.  For this, Bio-Synthesis, Inc. provides primers and probes (as well as synthetic RNA control) for COVID-19 diagnosis via RT-PCR assay.  For medicinal chemistry, it specializes in peptide synthesis, characterization, modification, purification to generate various peptide-based building blocks as well as pharmaceutical intermediates—in addition to peptide libraries, peptide arrays, peptidomimetics.   Antibody purification, characterization/quantification, modification and labeling are also offered.  It specializes in oligonucleotide modification and provides an extensive array of chemically modified nucleoside analogues (over ~200) including bridged nucleic acid (BNA).  A number of options are available to label oligonucleotides (DNA or RNA) with fluorophores either terminally or internally as well as conjugate to peptidesIt recently acquired a license from BNA Inc. of Osaka, Japan, for the manufacturing and distribution of BNANC, a third generation of BNA oligonucleotides.  To meet the demands of therapeutic application, its oligonucleotide products are approaching GMP grade.  Bio-Synthesis, Inc. has recently entered into collaborative agreement with Bind Therapeutics, Inc. to synthesize miR-21 blocker using BNA for triple negative breast cancer.  The BNA technology provides superior, unequalled advantages in base stacking, binding affinity, aqueous solubility and nuclease resistance.  It also improves the formation of duplexes and triplexes by reducing the repulsion between the negatively charged phosphates of the oligonucleotide backbone.  Its single-mismatch discriminating power is especially useful for diagnosis (ex. FISH using DNA probe).  For clinical application, BNA oligonucleotide exhibits lesser toxicity than other modified nucleotides.









Davenport AP, Scully CCG, de Graaf C, Brown AJH, Maguire JJ.  Advances in therapeutic peptides targeting G protein-coupled receptors. Nat Rev Drug Discov. 19:389-413 (2020). PMID: 32494050

Han Y, Kral P.  Computational Design of ACE2-Based Peptide Inhibitors of SARS-CoV-2.  ACS Nano 4, 5143-5147 (2020). https://pubs.acs.org/doi/10.1021/acsnano.0c02857

Inamoto I, Shih JA.  Peptide therapeutics that directly target transcription factors.  Peptide Sci.  111:1-11 (2018).  https://onlinelibrary.wiley.com/doi/epdf/10.1002/pep2.24048

Lee AC, Harris JL, Khanna KK, Hong JH.   A Comprehensive Review on Current Advances in Peptide Drug Development and Design.  Int J Mol Sci. 20:2383 (2019).  PMID: 31091705

Zhang G, Pomplun S, Loftis AR, Tan X, Loas A, Pentelute BI.  Investigation of ACE2 N-terminal fragments binding to SARS-CoV-2 Spike RBD.  bioRxiv (2020).