Development of a novel angiotensin converting enzyme 2 stimulator with broad implications in SARS-CoV2 and type 1 diabetes.
Niwanthi RajapakseHaru NomuraMelanie WuJiangning SongAndrew HungShirley TranHang TaFahima AktherYuao WuMatt D JohansenKeng ChewVinod KumarTrent M WoodruffRichard J ClarkJohannes KoehbachBruno LomonteCarlos RosadoMerlin ThomasMarion BoudesCyril ReboulLachlan D RashLinda GalloSumia EssidDominika ElmlundStefan MiemczykNicole HansbroBernadette SaundersWarwick BrittonPeter D SlyAyaho YamamotoJulián FernándezPeter Michael MoyleKirsty ShortPhilip HansbroSanjaya KuruppuIan SmithPublished in: Research square (2023)
Angiotensin-converting enzyme 2 (ACE2) is protective in cardiovascular disease, lung injury and diabetes yet paradoxically underlies our susceptibility to SARs-CoV2 infection and the fatal heart and lung disease it can induce. Furthermore, diabetic patients have chronic, systemic inflammation and altered ACE2 expression resulting in increased risk of severe COVID-19 and the associated mortality. A drug that could increase ACE2 activity and inhibit cellular uptake of severe acute respiratory syndrome coronavirus 2 (SARs-CoV2), thus decrease infection, would be of high relevance to cardiovascular disease, diabetes and SARs-CoV2 infection. While the need for such a drug lead was highlighted over a decade ago receiving over 600 citations, 1 to date, no such drugs are available. 2 Here, we report the development of a novel ACE2 stimulator, designated '2A'(international PCT filed), which is a 10 amino acid peptide derived from a snake venom, and demonstrate its in vitro and in vivo efficacy against SARs-CoV2 infection and associated lung inflammation. Peptide 2A also provides remarkable protection against glycaemic dysregulation, weight loss and disease severity in a mouse model of type 1 diabetes. No untoward effects of 2A were observed in these pre-clinical models suggesting its strong clinical translation potential.
Keyphrases
- angiotensin converting enzyme
- respiratory syndrome coronavirus
- sars cov
- type diabetes
- cardiovascular disease
- angiotensin ii
- coronavirus disease
- glycemic control
- weight loss
- cardiovascular events
- mouse model
- drug induced
- amino acid
- cardiovascular risk factors
- poor prognosis
- insulin resistance
- heart failure
- oxidative stress
- bariatric surgery
- coronary artery disease
- risk factors
- climate change
- emergency department
- adverse drug
- gastric bypass