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Is drug repurposing really the future of drug discovery or is new innovation truly the way forward?

Drug discovery process is a costly and time-consuming task. An average of 12–15 years is required for a drug to be approved [1]. The investment required to get it increases exponentially since the drug enters in the regulatory development phase, previous to clinical phases, till the drug is finally approved to be marketed by the corresponding regulatory agencies. Furthermore, translation of results from sophisticated animal and cellular models to the clinical setting is scarce [2]. In that scenario, drug repurposing is gaining stage in the last years as a way to speed the drug discovery process [3]. Particularly gloomy is the case of rare and neglected diseases, which affects a reduced number of patients or lowincome populations. Thus, due to the high costs associated with new drug development and low expected revenues in these particular cases, pharma companies cannot afford a big investment in these diseases. Furthermore, in terms of time, 12–15 years are not acceptable to face health emergencies such as the present COVID-19 pandemic or Ebola’s outbreaks. In these situations, drug repurposing of approved drugs with an acceptable margin of safety is an excellent alternative to find therapeutic treatments for a given unmet and urgent medical need. Drug repurposing consists of finding new therapeutic uses for old drugs different from the original medical indication. Discovery of new molecular targets and pharmacological actions represents novel therapeutic opportunities for clinically used drugs. The main advantage of this strategy is the existing knowledge of the known drug in terms of safety profile, clinical use, and manufacture processes. Altogether, it could be possible to skip preclinical development and phase I clinical trials, entering directly into phase II clinical studies where the patients’ treatment will confirm or not the therapeutic efficacy. This approach allows a faster drug development with a significant investment and risk reduction [4]. Initially, drug repurposing was mainly due to serendipitous discoveries of surprising effects observed after the treatment with a given drug. As ‘chance favors only the prepared mind’ [5], serendipity has produced great advances in the history of medicine and selective optimization of side activities of drug molecules is an intelligent strategy for the generation of new drugs [6]. That may be the case of the blockbuster sildenafil designed as an hypertensive agent [7], dimethyl fumarate, a recently new oral drug for multiple sclerosis [8] used in Europe to treat psoriasis for several decades [9] or more recently, the only antiviral FDA-approved drug against COVID-19, remdesivir, which was in final clinical trials for Ebola virus infection [10]. Nowadays, the situation has evolved, and a rational and systematic approach is behind most of the drug repurposing campaigns. Libraries of approved compounds are available from different commercial sources and a number of computational and highcontent screening methods are currently used to discover new indications for existing molecules [11]. When a hit emerges from a drug repurposing strategy, it is already the candidate for clinical development, sometimes entering directly in the last phases. Far from being optimal, this approach is very useful to find treatments for unmet diseases and health emergencies [12]. Despite significant advantages, drug repurposing also suffers some issues important to be considered. On one hand, there are no possibilities for optimization without losing the repurposing potential because any minimal change in the chemical structure means a new full manufacture process validation and preclinical safety development. On the other, the fact that a drug usually targets a minimum of five different proteins allows to expand the drug’s applications, but can also have side effects when the indications and doses are changed [13]. Furthermore, as candidates to be repurposed are usually patented or off-patent, the intellectual property protection for the new indication is not strong enough [3]. Today, de novo drug discovery process affords important differences with the aforementioned strategy (Figure 1), not only in terms of time and cost but also from the innovation point of view. In traditional drug discovery, the first step in the process is hit identification that moves forward to a subsequent hit-to-lead step to extensively search the optimized candidate for further pharmaceutical development. In this step not only increase in target potency and selectivity is noted for but also drug-like properties. The in-depth study around the biological mechanism of action of the hits also provides new therapeutic