The most advanced antiviral molecules addressing major SARS-CoV-2 targets (Main protease, Spike protein, and RNA polymerase), compared with proteins of other human pathogenic coronaviruses, may have a short-lasting clinical efficacy. Accumulating knowledge on the mechanisms underlying the target structural basis, its mutational progression, and the related biological significance to virus replication allows envisaging the development of better-targeted therapies in the context of COVID-19 epidemic and future coronavirus outbreaks. The identification of evolutionary patterns based solely on sequence information analysis for those targets can provide meaningful insights into the molecular basis of host-pathogen interactions and adaptation, leading to drug resistance phenomena. Herein, we will explore how the study of observed and predicted mutations may offer valuable suggestions for the application of the so-called "synthetic lethal" strategy to SARS-CoV-2 Main protease and Spike protein. The synergy between genetics evidence and drug discovery may prioritize the development of novel long-lasting antiviral agents.