| Just a little clarification. These renin-angiotensin terms are totally confusing (due to how similar they all are!) and from my correspondence with physicians, many of them even get them mixed up! Virus binds to and downregulates ACE2. ACE2 converts Ang II to Ang 1-7. Ang II binds to AT1R and AT2R receptors: https://twitter.com/__philipn__/status/1229607854232850432?s... Pic for clarity. When there’s less ACE2, and in general due to immune response, there will be more Ang II to bind to AT1R. This AT1R binding may create the lung injury seen with the virus. The idea is that by blocking AT1R with an ARB type drug you don’t stop the virus from entering a cell, but you instead stop the body’s pathological response to the virus. After all, most viruses don’t kill us, and our immune system - if it doesn’t over react - will usually kill a thing if it has enough time and the virus isn’t “special” like HIV or herpes (that’s my general, non expert understanding!) While it seems smart to try and inhibit ACE2 directly, there are a couple problems with this I see: 1. It may be pathological. More Ang II to bind to AT1R, you might end up way worse off. ACE2 is the “good” ACE, and all the evidence we have seems to suggest that a reduction in the ACE2:ACE ratio will make tissue fibrosis, death, etc worse. This happens in the heart and lungs in mouse models. 2. Small molecule ACE2 inhibitors bind to the C shaped area of the ACE2 enzyme, while the virus attaches to the back. So they likely may not inhibit cell entry: https://twitter.com/robertlkruse/status/1230577662751641601?... The best silver bullet bet here is ACE2-fc, which isn’t a small molecule. This is a soluble form of the ACE2 protein along with an fc. this gives it a longer half life in the body. This would likely: 1. Stop virus cell entry by neutralizing the virus- virus binds to ACE2-fc instead of the cell ACE2. 2. Stop potential lung damage from AT1R activation. Both 1 and 2 have been shown in some models. It is now being tested in vitro. Next animals. Chinese are testing non-fc form, ACE2 directly, but requires IV drip. Testing now directly in humans! 7 day trial. See twitter for more on this: https://twitter.com/__philipn__ If you’re a funder, VC and you’re reading this: The scientist at John Hopkins who’s developing ACE2-fc is looking for funding. He’s working with Chinese biotech firms now to do the testing. Please comment here and I will connect you. |