Michael Gwarisa
Amid growing global pressure to make Lenacapavir more affordable, researchers at the Manchester Institute of Biotechnology have developed a new method that could significantly reduce the cost and improve the sustainability of manufacturing the long-acting HIV prevention drug.
Supported by funding from the Gates Foundation, the scientists applied engineering biology, a rapidly advancing field that harnesses natural biological processes to produce chemicals and materials, to simplify the production of Lenacapavir.
The findings were published in the Journal of the American Chemical Society (JACS), where the research team, led by Professors Anthony Green and Nick Turner, outlined how they used directed evolution to engineer a specialised aminotransferase enzyme. This innovation accelerates production while lowering manufacturing costs, offering a pathway to improved global access to the drug.
Lenacapavir, recently approved by the United States Food and Drug Administration and the United Kingdom Medicines and Healthcare products Regulatory Agency, is a twice-yearly injectable used in HIV prevention. It has demonstrated exceptionally high efficacy in pre-exposure prophylaxis trials. While royalty-free licensing agreements are already in place to allow generic production in more than 120 low- and middle-income countries, the high cost of producing its active pharmaceutical ingredient continues to limit widespread availability.
Lenacapavir is made up of four key building blocks, with its central core presenting a major manufacturing challenge. This core relies on a chiral amine, a molecule that exists in two mirror-image forms. In pharmaceutical production, only one of these forms is effective, making precision essential.
Traditional synthesis methods rely on complex, multi-step chemical processes that are both time-consuming and expensive. The structural complexity and chirality of Lenacapavir further complicate production, driving up costs.
Biocatalysis offers an alternative approach. By using enzymes to facilitate chemical reactions, scientists can achieve faster, more efficient, and potentially cheaper production processes.
Professor Anthony Green, Director of the Manchester Institute of Biotechnology, said biocatalysis presents a promising solution for manufacturing complex pharmaceutical compounds.
“Biocatalysis offers a sustainable and economical way to make complex molecules, but tailoring enzymes to handle challenging pharmaceutical intermediates requires a deep understanding of enzyme structure, function and evolution. By engineering this aminotransferase, we have created a practical route to a key component of Lenacapavir that could help lower manufacturing costs and expand access to this life-saving therapy,” he said.
To achieve this, the research team used directed evolution, a technique that accelerates natural selection in the laboratory. Through a process known as substrate walking, they began with an enzyme that initially showed no activity on the target compound.
Over eight rounds of evolution, the team screened more than 12,000 enzyme variants and introduced ten strategic mutations. These changes gradually improved the enzyme’s performance, enhanced its stability, and reshaped its active site to accommodate the bulky molecular structure required for Lenacapavir production.
The final enzyme demonstrated strong performance, converting 98 percent of the starting material and delivering yields above 90 percent. It also achieved over 99 percent enantiomeric excess, ensuring that the correct molecular form was produced. Further testing under industrial conditions confirmed its potential for large-scale manufacturing.
Using X-ray crystallography, the researchers also mapped the enzyme’s three-dimensional structure, providing insights into how the mutations enabled it to process the target molecule. This structural understanding is expected to support future enzyme design and optimisation efforts.
Moving towards large-scale production
The research team is now working with industrial partners to transition the process from laboratory experiments to full-scale biomanufacturing. Importantly, the details of the method have been made publicly available to encourage adoption.
Companies interested in producing Lenacapavir using this approach can obtain enzyme samples through Prozomix. If successfully implemented at scale, the process could offer a shorter, cleaner, and more cost-effective manufacturing route, helping to expand access to long-acting HIV prevention globally.
Lenacapavir represents a new class of antiretroviral drugs and offers long-acting protection against HIV transmission, making it a critical tool in global HIV prevention strategies.
This research was published in:
Journal of the American Chemical Society (JACS)
Full title of the paper:
Biocatalytic Production of a Key Chiral Intermediate of the HIV Capsid Inhibitor Lenacapavir
DOI:
10.1021/jacs.6c02519
URL:
https://pubs.acs.org/doi/10.1021/jacs.6c02519
