A look at peptide products to protect against diseases and insects

It’s been known for many years that various organisms produce defensive peptides. A team of Chinese scientists, in their 2023 review of peptide advancements in crop products, note that ‘naturally-occurring antimicrobial peptides (AMPs) mediate the innate host defense and can be used as immune inducers. Given their high specificity, rapid degradation and efficacy, AMPs are expected to be a promising first line of defense against fungi, viruses and bacteria.’

This team, headed by Dr. Yi-Meng Zhang at the Innovation Center of Pesticide Research at China Agricultural University in Beijing, also notes that the US, China, Germany, France, Italy, India and Japan are some of the leading countries in the area of peptide crop protection product R&D.

There are now over 3,400 AMPs logged in an antimicrobial peptide database

There are now over 3,400 AMPs logged in an antimicrobial peptide database managed by the University of Nebraska. Of these, about 29% are plant-derived, 16% are from animals (including mammals, frogs and insects) and about 5% are from microbes.

The rest? They are synthetic, about 50% of the total.

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Synthetic production

Since companies around the world began development of synthetic peptides in earnest just a few short years ago, about 20 have been produced. Some are currently undergoing tests for stability and efficacy, some are already awaiting regulatory approval and some have already reached various markets.

For example, the peptide insecticide called Spear LEP is derived from a neuropeptide of the venom of the Blue Mountains funnel-web spider. It is available for use in the US and beyond, for tree nuts, fruits, vegetables and other high-value specialty crops. It won the Best New Biological Agent Award in 2021 from the Crop Science Forum & Awards. A broad bio-fungicide called Quillibrium won in 2022. It has been marketed in Chile, Mexico and other countries, while it awaits US regulatory approval.

Problad Plus is another peptide bio-fungicide. It controls serious pathogens such as powdery mildew and gray mold in crops such as strawberries, grapes, tomatoes and stone fruit by causing damage to cell walls and membranes.

Challenges and solutions

According to Dr. Kyle Schneider, there are three main challenges to further development of peptide crop protection products. Schneider, a senior scientist of peptide development at Vestaron Corporation (maker of Spear LEP and other bio-products), lists bioavailability (the fraction of an administered compound that reaches the systemic circulation of the target), cost and regulatory hurdles.

Bioavailability has been a significant barrier in particular to the commercialization of peptide bio-insecticides, but progress is steadily being made. Schneider points to the high bioavailability of peptides such as the recently-approved ‘GS-w/k-Hxtx-Hv1a.’ It targets the same receptor in the insect body that’s targeted by two major classes of synthetic insecticides, and can kill insects on contact in a commercial formulation.

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Costs for spraying

However, the cost to spray some peptide bio-products at the application rate needed to ensure adequate contact with target insects can be too high, says Schneider. There are some novel solutions are being developed to ensure appropriate delivery at an affordable price. For example, the same peptide mentioned above (GS-w/k-Hxtx-Hv1a) has been successfully combined with microbial Bacillus thuringiensis, states Schneider, “dramatically reducing necessary peptide application rates by permeabilizing the insect gut and increasing peptide access to the target.” Pairing a microbial with a peptide bio-insecticide also means the environmental safety profile of the product is maintained.

Zhang and his colleagues also point to the use of different formulations, such as suspension agent, microemulsion and capsule suspension, which “can protect peptide molecules from degradation by environmental factors such as water, UV, temperature and metabolic enzymes. This not only enhances stability but also improves bioavailability.”

Combining two peptides can also work

Combining two peptides can also work. For example, applying the rainfast peptide thanatin with a product called ‘dermaseptin 01’ enables good adherence on soybean leaves, inhibiting the germination of spores that cause Asian soybean rust. “In addition, peptide formulates mixed with chemical pesticides via different mechanisms can expand the activity spectrum,” note the Chinese team, “and also delay resistance”.

Drug delivery systems (DDS) with ‘controlled release technologies’ such as hydrogels, cubosomes, and nanocarriers can also be used to deliver peptides.

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Reduced costs

Returning to cost as a barrier to further peptide crop protection product development, as peptides gain traction, the general cost of their production is steadily coming down.

Mikael Courbot, Chief Technology Officer of Micropep (based in France and the US), announced last year that their technology enables them to “manufacture micropeptides at scale with a 100x improvement in cost compared to chemical synthesis.”

The team from China also notes that synthetic peptides have a ‘high targeting affinity,’ meaning that only “a very small amount of peptide is sufficient to control weeds, pathogens, and insects.” Zhang and his colleagues add in their paper that “cost may be more competitive than existing pesticides due to the low dosage when peptides are completely or partially fermented.”

Technology more accessible

On the subject of fermentation, Schneider says the cost to manufacture peptides using microorganisms in large bioreactors has dropped substantially over the last decade. “It is due to this increase in manufacturing capacity and cost reduction that has allowed the technology to be accessible for crop protection and not just for human therapeutics,” he says.

“Still, costs must be reduced further for true cost comparability with synthetic chemicals in commodity crops (corn, soy, wheat, cotton, etc.),” he stresses. “Manufacturing by fermentation brings us close to cost parity to chemicals, but a small gap still exists. This gap is most challenging in commodity crops where grower inputs have a larger financial impact. However, based on recent trends in bioreactor costs, it is my view that this cost difference will become negligible within the next 5-10 years.”

Regulatory approval

Regulatory approval is the third major challenge facing peptide crop protection product developers, in Schneider’s view.

Right now, the US and the EU are developing new appropriate approval pathways for these new classes of biologicals. Regarding US progress, Schneider explains that the federal government has created the ‘Emerging Technologies’ branch within the Pesticides division responsible for developing the frameworks for assessing new technologies. “This branch was, in part, responsible for developing the framework for regulating Vestaron’s Spear peptide and Greenlight Bio’s Calantha RNAi biopesticides,” he says.

Challenges

At the same time, Schneider warns that new frameworks can create challenges. “Experts and knowledge about the new technology may not yet exist within regulatory agencies, resulting in the potential for delays, or worse, stifled innovation,” he says.

Peptides will likely become mainstream tools for plant protection in the future

Regulatory agencies should be transparent, he says, which gives the maximum amount of certainty possible to product developers as they navigate the evolving regulatory process.

It seems that even though there are challenges to peptide product development – delivery to the target pest or pathogen, costs and regulatory approval – these challenges are being met and many more peptide crop protection products are surely coming to market. Indeed, as the team from China notes, “peptides will likely become mainstream tools for plant protection in the future.”