6 Conclusions and future directions The SARS‐CoV‐2 outbreak has caused worldwide disruption and was recently declared a global pandemic by the World Health Organization (WHO) owing to its rapid spread and high fatality rate. As there is no effective treatment to date, the number of infections continues to rise globally. This has led numerous research groups around the world to prioritize the identification and development of new therapeutics against COVID‐19. Although it is often considered the most promising method to prevent or contain future coronavirus outbreaks, an all‐round anti‐CoV vaccine is possibly a long way away. Small molecule drugs have the potential to be effective, rapidly produced, and widely available. Indeed, several small molecules have been investigated and advanced to clinical trials for the treatment of COVID‐19, selected drug candidates are indicated in Table 3 (https://covid-19.heigit.org/clinical_trials.html). Table 3 Selection of molecules investigated in ongoing clinical studies (July, 2020) Name Structure Description Recent trials Azithromycin Macrolide antibiotic IRCT20200428047228N2 NCT04405921 EUCTR2020‐001605‐23‐ES Favipiravir Broad spectrum antiviral drug NCT04434248 ChiCTR2000033491 NCT04425460 Triazavirin Broad‐spectrum antiviral drug ChiCTR2000030001 Umifenovir Antiviral drug IRCT20200523047550N1 IRCT20151227025726N15 IRCT20200325046859N2 Baloxavir marboxil Antiviral drug ChiCTR2000029548 ChiCTR2000029544 Remdesivir Antiviral drug NCT04431453 NCT04409262 NCT04410354 Ribavirin Antiviral drug IRCT20200324046850N2 ChiCTR2000030922 Lopinavir/ritonavir Anti‐HIV combination medication NCT04403100 NCT04376814 Celecoxib COX‐2 selective NSAID ChiCTR2000031630 Chloroquine Antimalarial drug EUCTR2020‐001441‐39‐IT NCT04447534 NCT04443270 Hydroxychloroquine Antimalarial drug EUCTR2020‐001558‐23‐IT EUCTR2020‐001441‐39‐IT EUCTR2020‐001501‐24‐IT Mefloquine Antimalarial drug EUCTR2020‐001194‐69‐ES Ivermectin Broad‐spectrum antiparasitic drug NCT04445311 NCT04435587 NCT04431466 Colchicine Broad‐spectrum anti‐inflammatory drug NCT04416334 EUCTR2020‐001841‐38‐ES IRCT20190810044500N5 Corticosteroids (misc.) Broad‐spectrum anti‐inflammatory drug IRCT20151227025726N17 NCT04395105 IRCT20120215009014N354 Pirfenidone Antifibrotic, anti‐inflammatory drug IRCT20200314046764N1 ChiCTR2000031138 Tranilast Anti‐inflammatory drug ChiCTR2000030002 Selinexor Anticancer drug NCT04355676 NCT04349098 EUCTR2020‐001411‐25‐GB Valsartan Angiotensin II receptor antagonist DRKS00021732 NCT04335786 Dipyridamole PDE3 inhibitor NCT04424901 NCT04391179 Vidoflumidus (IMU‐838) Investigational drug EUCTR2020‐001264‐28‐HU Azvudine Investigational antiviral ChiCTR2000032769 NCT04425772 ChiCTR2000030487 EIDD‐2801 Investigational antiviral NCT04405570 NCT04405739 NCT04392219 John Wiley & Sons, Ltd. This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency. As outlined in this review, inhibitors of important viral enzymes or structures, such as Mpro, PLpro, or RdRP have displayed encouraging activity against various human‐infecting CoVs. Since, both contagious viruses, SARS‐CoV‐1 and SARS‐CoV‐2, have a similar mechanism of infection; and both share the same human receptor, ACE2, for viral entry, for example—already developed inhibitors against the former could potentially be used to combat the latter. But despite the efficacy demonstrated by many inhibitors of SARS‐CoV‐1, no specific prophylactic or postexposure therapy is currently available. The first step in the viral life cycle is the viral entry. It represents an attractive intervention point by blocking the RBD‐ACE2 interaction or the virus‐cell membrane fusion event. A large number of inhibitors, including peptides, antibodies, small‐molecule compounds, and natural products have been identified to hamper viral entry. Some of the peptides and antibodies displayed substantial anti‐SARS activity and are therefore considered promising entry inhibitors with high potencies in the low micromolar range. Despite the apparent match of SARS‐CoV‐2 S and ACE2, other possible viral entry receptors should not be left unexplored. The glucose‐regulated protein 78 (GRP‐78, aka HSPA5), for instance, is employed as a coreceptor for entry by several viruses, including bat‐CoVs and MERS‐CoV, 260 and a study predicted that SARS‐CoV‐2 S might utilize this mechanism as well. 261 Elevated levels of GRP‐78 in COVID‐19 patients suggest a supplementary link. 262 Although as of yet unconfirmed, the development of therapeutics against additional targets like GRP‐78 should receive due attention. Viral proteases are another very important target for the development of antiviral therapies, as they are directly involved in the viral replication processes. Especially the Mpro is one of the best‐characterized viral targets, and numerous medicinal chemistry efforts have been already reported for the past outbreaks of SARS‐1 and MERS. Main proteases are highly conserved among other CoVs, which allows the development of broad spectral antiviral agents. Moreover, no human protease analog to the Mpro is known. Thus, drugs targeting Mpro could be highly virus‐selective and safe. In light of the urgency of the current outbreak, repositioning of already approved drugs is becoming a popular approach due to the availability of toxicity and safety data. Drug repurposing has become fashionable, promising quick solutions to complicated questions. Old and, presumably, safe drugs are proclaimed miracle cures. The reality is a different one: Widely employed broad‐spectrum antiviral drugs, such as (hydroxy)chloroquine, favipiravir, ribavirin, or umifenovir were reported to be effective against SARS‐CoV‐2, but could not convince in clinical trials yet. Clinicians are faced with an avalanche of contraindications and a myriad of case reports to choose the right drug. The drug repositioning strategy is, therefore, not a sound scientific path to a cure. At best, it can provide a basis for extensive future research in all related fields, including synthetic organic medicinal chemistry. A new problem with the current COVID‐19 outbreak is related to the spread of scientific information. When initial unfounded speculations about the alleged dangers of antihypertensive therapies with ACEis and ARBs were widely publicized in the media they caused great uncertainty among patients. Impetuous communications such as these can have serious consequences and should not be proclaimed carelessly. As it turns out, the benefits of continued antihypertensive therapy with these medicines in COVID‐19 patients far outweigh their risks. There is even evidence of additional protective effects of ACEis and ARBs in this cohort, although the clinical relevance of this has yet to be investigated. It is clear that governments and societies all over the world have been surprised by the recent coronavirus outbreak—as they were by the SARS outbreak in 2003 and the MERS epidemic in 2013. Human‐infecting CoVs are on the rise, but quickly forgotten once life returns to normal. However, this problem will not disappear by itself, but likely increase in intensity. Viral spillover events are expected to increase in frequency as humans continue to invade new territories. We hope that, this time, the world will heed nature's warning to finance and conduct groundbreaking research on CoVs and their disease patterns. Only with a profound understanding of the viral life cycle and the affected human physiology we can prevent and control future outbreaks.