key: cord-0795598-4d3opuik authors: Bhullar, Khushwant S.; Drews, Steven J.; Wu, Jianping title: Translating bioactive peptides for COVID-19 therapy date: 2020-10-21 journal: Eur J Pharmacol DOI: 10.1016/j.ejphar.2020.173661 sha: 88bfe918e478cc3f928514fefcbca304230a7db8 doc_id: 795598 cord_uid: 4d3opuik COVID-19 (Coronavirus disease 2019) is a global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a positive-sense RNA virus. This virus has emerged as a threat to global health, social stability, and the global economy. This pandemic continues to cause rampant mortality worldwide with the dire urgency to develop novel therapeutic agents. To meet this task, this article discusses advances in the research and potential application of bioactive peptides for possible mitigation of infection by SARS-CoV-2. Growing insight into the molecular biology of SARS-CoV-2 has revealed potential druggable targets for bioactive peptides. Bioactive peptides with unique amino acid sequences can mitigate such targets including, type II transmembrane serine proteases (TMPRSS2) inhibition, furin cleavage, and renin-angiotensin-aldosterone system (RAAS) members. Based on current evidence and structure-function analysis, multiple bioactive peptides present potency to neutralize the virus. To date, no SARS-CoV-2-explicit drug has been reported, but we here introduce bioactive peptides in the perspective of their potential activity against SARS-CoV-2 infection. Since its initial presentation in Wuhan, China, COVID-19 respiratory disease has generated 36 enormous global concern and developed into a worldwide pandemic (Lu et al., 2020) . spread, the susceptibility of all age groups was evident to infections through inhalation of 47 infectious droplets (Rothe et al., 2020) . Further, the virus remains stable on surfaces for days 48 and infection may even be acquired by touching the contaminated areas (Rothe et al., 2020 ; 49 Singhal, 2020). Clinically, COVID-19 infection may exhibit an asymptomatic state, as well as a 50 wide range of symptoms from mild disease to acute respiratory distress and even multi-organ 51 dysfunction . However, significantly milder pathogenesis has been observed 52 in neonates, infants, and children, compared to their adult counterparts, yet, as we learn more, 53 this may be an overgeneralization Zeng et al., 2020) . 54 At the molecular level, pathogenesis commences with the binding of the virus to cellular 55 receptors, hence, the receptor recognition is a key element of host tropism. Also, the gain-of-56 function of a virus to attach to the receptor equivalents in other species is a prerequisite for 57 inter-species transmission (Lu et al., 2015) . The receptor binding domain (RBD) of SARS-CoV-2, 58 like SARS-CoV, binds with the receptor of angiotensin-converting enzyme 2 (ACE2) (Wrapp et 59 al., 2020). ACE2, a metallopeptidase, since its discovery in 2000, is a well-studied homolog of Thus, the complicated nature of COVID-19 pathology and the balance between ACE-2 93 and Ang II must be addressed in treatments involving the blocking of ACE2 binding. Hence, it is 94 safe to say that ACE2 does not appear as a tidy villain in COVID-19 story. Even some scientists 95 have begun to think the RAAS targeting medicines, even those increasing ACE2, maybe a good 96 therapy for COVID-19 (Sanchis-Gomar et al., 2020). Further, clinicians are now beginning to 97 suspect that an imbalance in Ang II clearance in our bodies, due to ACE2 and SARS-CoV-2 98 interaction, could be skyrocketing Ang II and propelling cytokine storm mediated inflammation 99 and consequential severe lung and heart damage seen in advanced COVID-19 patients. ). As the ACE2/Ang 1-7/MasR axis has an opposing effect on the ACE/Ang II/AT1R axis, 160 therefore, targeting of the latter can mitigate downstream redox and vasoconstrictive stress. 161 Essentially, the clinical aim is to attain a balance between how much Ang II is expressed, and 162 how much is accumulated/processed (or managed via drugs). The ARBs have an edge over ACE 163 inhibitors as the latter is linked with higher adverse events and particularly bradykinin and 164 angioedema accumulation prompted cough, which can further spread the virus (Messerli et al., 165 2018). Overall, it has been hypothesized but unconfirmed that persistent Ang II surge may be in 166 part responsible for pulmonary injury in COVID-19 patients. Therefore, the prospective use of 167 peptides-based Ang II antagonists (AT1R inhibitors) to counterbalance RAAS is a rational 168 pharmacological approach. Similarly, Gurwitz recommended using available AT1R blockers, for 169 instance, losartan, as a pharmacological intervention in COVID-19 infections (Gurwitz, 2020) . 170 The details of the current evidence regarding the ability of peptides to counter Ang-II are 171 discussed in the subsequent section(s). (Li et al., 2005) . While belonging to separate taxonomical genera, both SARS-CoV and 295 hCoV-NL63 interact with ACE2 for cellular entry (Singhal, 2020) . For the SARS-CoV-2 to 296 successfully enter the cell(s) following the initial interaction, the spike protein has to be primed CoV-2 pathology. Global health and drug/nutraceutical discovery will never be the same after 380 J o u r n a l P r e -p r o o f the COVID-19 pandemic, it cannot be. We should no longer pay lip service to alternative and 381 innovative interventions in the mitigation of COVID-19. Whether novel natural bioactive or 382 rationally designed peptides, they must be explored further. 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