The World Health Organization declared the SARS-CoV-2 outbreak a Public Health Emergency of International Concern at the end of January 2020 and a pandemic two months later. The virus primarily spreads between humans via respiratory droplets, and is the causative agent of Coronavirus Disease 2019 (COVID-19), which can vary in severity, from asymptomatic or mild disease (the vast majority of the cases) to respiratory failure, multi-organ failure, and death. Recently, several vaccines were approved for emergency use against SARS-CoV-2. However, their worldwide availability is acutely limited, and therefore, SARS-CoV-2 is still expected to cause significant morbidity and mortality in the upcoming year. Hence, additional countermeasures are needed, particularly pharmaceutical drugs that are widely accessible, safe, scalable, and affordable. In this comprehensive review, we target the prophylactic arena, focusing on small-molecule candidates. In order to consolidate a potential list of such medications, which were categorized as either antivirals, repurposed drugs, or miscellaneous, a thorough screening for relevant clinical trials was conducted. A brief molecular and/or clinical background is provided for each potential drug, rationalizing its prophylactic use as an antiviral or inflammatory modulator. Drug safety profiles are discussed, and current medical indications and research status regarding their relevance to COVID-19 are shortly reviewed. In the near future, a significant body of information regarding the effectiveness of drugs being clinically studied for COVID-19 is expected to accumulate, in addition to information regarding the efficacy of prophylactic treatments.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak resulted in hundreds of millions of coronavirus cases, as well as millions of deaths worldwide. Coronavirus Disease 2019 (COVID-19), the disease resulting from exposure to this pathogen, is characterized, among other features, by a pulmonary pathology, which can progress to “cytokine storm”, acute respiratory distress syndrome (ARDS), respiratory failure and death. Vaccines are the unsurpassed strategy for prevention and protection against the SARS-CoV-2 infection. However, there is still an extremely high number of severely ill people from at-risk populations. This may be attributed to waning immune response, variant-induced breakthrough infections, unvaccinated population, etc. It is therefore of high importance to utilize pharmacological-based treatments, despite the progression of the global vaccination campaign. Until the approval of Paxlovid, an efficient and highly selective anti-SARS-CoV-2 drug, and the broad-spectrum antiviral agent Lagevrio, many pharmacological-based countermeasures were, and still are, being evaluated in clinical trials. Some of these are host-directed therapies (HDTs), which modulate the endogenic response against the virus, and therefore may confer efficient protection against a wide array of pathogens. These could potentially include Biological Warfare Agents (BWAs), exposure to which may lead to mass casualties due to disease severity and a possible lack of efficient treatment. In this review, we assessed the recent literature on drugs under advanced clinical evaluation for COVID-19 with broad spectrum activity, including antiviral agents and HDTs, which may be relevant for future coping with BWAs, as well as with other agents, in particular respiratory infections.