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Three years since its origin, despite the approval of vaccines and specific treatments against this new coronavirus, there are still high rates of infection, hospitalization, and mortality in some countries. COVID-19 is characterised by a high inflammatory state and coagulation disturbances that may be linked to purinergic signalling molecules such as adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine (ADO), and purinergic receptors (P1 and P2). These nucleotides\/nucleosides play important roles in cellular processes, such as immunomodulation, blood clot formation, and vasodilation, which are affected during SARS-CoV-2 infection. Therefore, drugs targeting this purinergic pathway, currently used for other pathologies, are being evaluated in preclinical and clinical trials for COVID-19. In this review, we focus on the potential of these drugs to control the release, degradation, and reuptake of these extracellular nucleotides and nucleosides to treat COVID-19. Drugs targeting the P1 receptors could have therapeutic efficacy due to their capacity to modulate the cytokine storm and the immune response. Those acting in P2X7, which is linked to NLRP3 inflammasome activation, are also valuable candidates as they can reduce the release of pro-inflammatory cytokines. However, according to the available preclinical and clinical data, the most promising medications to be used for COVID-19 treatment are those that modulate platelets behaviour and blood coagulation factors, mainly through the P2Y12 receptor.<\/jats:p>","DOI":"10.3390\/ijms24097865","type":"journal-article","created":{"date-parts":[[2023,4,26]],"date-time":"2023-04-26T02:30:52Z","timestamp":1682476252000},"page":"7865","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["A Systematic Review of the Role of Purinergic Signalling Pathway in the Treatment of COVID-19"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7877-0396","authenticated-orcid":false,"given":"Vitoria Guero","family":"Korb","sequence":"first","affiliation":[{"name":"Laborat\u00f3rio de Biologia Celular, Universidade Federal de Ci\u00eancias da Sa\u00fade de Porto Alegre (UFCSPA), Porto Alegre 90050-170, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2056-1556","authenticated-orcid":false,"given":"Iago Carvalho","family":"Schultz","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Biologia Celular, Universidade Federal de Ci\u00eancias da Sa\u00fade de Porto Alegre (UFCSPA), Porto Alegre 90050-170, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5688-3015","authenticated-orcid":false,"given":"Liziane Raquel","family":"Beckenkamp","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Biologia Celular, Universidade Federal de Ci\u00eancias da Sa\u00fade de Porto Alegre (UFCSPA), Porto Alegre 90050-170, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5987-3509","authenticated-orcid":false,"given":"M\u00e1rcia Ros\u00e2ngela","family":"Wink","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Biologia Celular, Universidade Federal de Ci\u00eancias da Sa\u00fade de Porto Alegre (UFCSPA), Porto Alegre 90050-170, RS, Brazil"},{"name":"Departamento de Ci\u00eancias B\u00e1sicas da Sa\u00fade, Universidade Federal de Ci\u00eancias da Sa\u00fade de Porto Alegre (UFCSPA), Rua Sarmento Leite, 245, Sala 304 Centro, Porto Alegre 90050-170, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3245","DOI":"10.1007\/s10067-022-06279-9","article-title":"The Relationship between COVID-19 and Fibromyalgia Syndrome: Prevalence, Pandemic Effects, Symptom Mechanisms, and COVID-19 Vaccines","volume":"41","author":"Kocyigit","year":"2022","journal-title":"Clin. 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