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The combination of a C-domain-selective ACEi plus an NEP inhibitor:

Decreases blood pressure and normalises contraction of the blood vessels without influencing vascular permeability and endothelial cell function
These features may be beneficial in the treatment of high blood pressure but without the side effects of cough and angioedema associated with the inhibition of NEP and the non-domain-selective inhibition of ACE
This combination therapy has important clinical relevance and may be a new approach in the treatment of hypertension and heart failure.

Background to ACE protein crystallisation and structure determination

For many years, the ACE crystal structure was a holy grail in both industry and academia because of the enormous importance of ACE as a therapeutic target. Efforts to crystallize ACE and determine its structure had been going on since the late 1980s in numerous laboratories and had all failed. The key problems included obtaining ACE in a form and in quantities sufficient to facilitate crystallization trials and in establishing crystallization conditions that would yield crystals suitable for x-ray diffraction.

The founders of AngioDesign developed innovative solutions that finally cracked the ACE structure problem. Large proteins like ACE are difficult to crystallize. The common somatic form of ACE contains more than 1,400 amino acids, as well as numerous complicated sugar residues, which hinder crystallization. To overcome these problems, the founders focused on the isolated C- and N-domains of ACE which were known to be independently active. Numerous minimally glycosylated protein forms were engineered and expressed for crystallisation trials, eventually producing diffraction-quality crystals.

The ACE crystals were exposed to high-energy x-rays in a synchrotron source, generating high-resolution diffraction patterns. Importantly, ACE was also co-crystallized with various types of ACE inhibitors, which would lead to crucial insights into how the active site functions and how to design improved inhibitors. The diffraction data were processed by sophisticated computer programs, which eventually produced a precise three-dimensional picture of the protein. This structure revealed the exact shape of ACE, how it is regulated, and how the active site, the business end of the enzyme, acts on the peptides that are its target. The way the active site functions is the key to rational drug design.

Using these techniques, the structures of both the C- and N-domains were solved. The two domains are highly similar but also reveal subtle yet significant differences. Detailed knowledge of these differences is essential for the design and synthesis of novel domain-selective inhibitors.

Against this background, the founders of AngioDesign are world leaders in enzyme structure determination and rational drug design. Two of the founders determined the crystal structure of ACE at an extremely high resolution (Natesh R., Schwager S.L., Sturrock E.D., Acharya K.R. Nature 421, 551-4, 2003).

The figure on the left is a cartoon representation showing an overview of the tACE co-crystal structure with lisW-S.
The figure on the right is a stick representation showing lisW-S interactions in the active site: comparison between N- and C-domain residues.

Using this unique knowledge of the three-dimensional structure of ACE, AngioDesign is developing domain-selective ACE inhibitors to lead to next-generation drugs that are novel, safer and more effective treatments. Patents have been granted on the enabling technology and classes of compounds crucial to the development of next-generation ACE inhibitors and more recent filings now include the combination of next-generation ACE inhibitors with other inhibitors, e.g. neprilysin (NEP).

Angiodesign’s rational drug design capabilities are complemented by deep and extensive expertise in medicinal chemistry, computational hit and lead selection, and preclinical pharmacokinetics (PK) and pharmacodynamics (PD) of leading drug candidates. Having ownership of the crystal structures of the C- and N-domains of ACE, as well as the proprietary right to use the information to design and synthesize C- and N-domain-selective ACE inhibitors, alone or in combination with other inhibitors, AngioDesign has a significant competitive advantage. Moreover, the company’s scientists and senior advisors possess know-how crucial for the rapid co-crystallization of ACE with novel domain-selective inhibitors as they are synthesized, which is essential for fine-tuning and lead optimization. Collectively, this should put AngioDesign in an unassailable position to develop its patented technology.

There are currently five patent families that make up the ACE patent portfolio. Patents have been granted on the enabling technology and classes of compounds crucial to the development of next-generation ACE inhibitors. The C-domain applications have been granted in eleven European countries, the United States, Canada, Australia and South Africa. In addition, a United States divisional application has been granted. N-domain applications have been granted in six European countries, the United States, Canada, Australia and South Africa. Both the Inhibitor 1 family and the Inhibitor 3 family have been granted in five European countries, the United States, Canada, Australia and South Africa. A patent application filed on the design and use of dual C-domain/NEP inhibitors was granted in the United States in 2021 and the company received Notice from the European Patent Office of their intention to grant a patent on this application in 2023.

Continuing R&D and Development Pipeline

AngioDesign’s near- to medium-term R&D objectives are:

Optimization of the co-crystallization of lisW-S and an NEP inhibitor
Deliver a new vasopeptidase inhibitor preclinical candidate
Conduct further tests for C-domain inhibitors in other disease areas. For example, AngioDesign is currently conducting collaborative research work to evaluate the effects of lisW-S in immune response
Progress N-domain inhibitors for the treatment of fibrosis.

Collaborations in place with UCT and its H3D Drug Discovery facility, the University of Bath, the University of Glasgow, Attoquant Diagnostics, Syngene, Cedars-Sinai Medical Center and others will continue to build effective new classes of products.

Primary Products lisW-S and lisW-S combined with an NEP inhibitor

Preclinical activity shows proof of concept for AngioDesign’s molecule: lisW-S (lisinopril-tryptothan (Lis-Trp)), which:

Is a novel C-domain ACE inhibitor with no preclinical signs of toxicity observed in good laboratory practice (GLP) toxicology tests
After short-term treatment causes a 15% decrease in systolic BP, similar to that of lisinopril
Shows clear evidence for decreased levels of bradykinin following treatment with lisW-S
Combined with an NEP inhibitor is antihypertensive and cardioprotective but without affecting endothelial vasodilation.

Market Opportunity

There is renewed interest in CVD development based on recent successes and advances in understanding. This environment opens the door for new therapies based on AngioDesign’s novel domain-selective ACE inhibitors, initially for cardiovascular applications, and subsequently for wider therapeutic applications. AngioDesign estimates that current drugs that are “old technology” and have significant side effects will be replaced by domain-selective ACE inhibitors. ACE is a high-value drug target and global drug sales are forecast to grow to $40bn. by the end of this decade for antihypertensives and to over $10bn. by 2026 for heart failure. The introduction of a patented next-generation ACE inhibitor with significantly improved tolerability that can be clearly differentiated in the market will have enormous upside potential.

Selected Publications

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