Viral diseases pose a huge threat to global human health. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has claimed over 4 million lives and caused over 198 million cases worldwide since its emergence in 2019.1 Zika virus (ZIKV) is a mosquito borne disease prevalent in tropical regions of South America, Africa and South-East Asia. Infections have been linked to neurological disorders, such as microcephaly in infants and Guillain-Barré syndrome in adults.2 This research explores the use of retro-inverso peptidomimetics with N‑terminal warheads as inhibitors of the NS2B-NS3 protease of ZIKV and the main protease (Mpro) of SARS‑CoV-2, both essential enzymes for viral replication. Retro-inverso peptides involve the reversal of the C- and N-termini and the inversion of stereochemistry through the incorporation of D-amino acids. In comparison to native L-peptide sequences, they are resistant to proteolysis and are less susceptible to breakdown in human plasma.3 Short retro-inverso peptides mimicking the preferred protease substrate sequence from P4 to P1´ were synthesised with N‑terminal covalent warheads including α‑ketoamides, Michael acceptors and nitriles. The synthesis of α‑ketoamides and Michael acceptors was achieved throughout solid-phase peptide synthesis using α‑keto acids and standard coupling conditions. Ongoing research is exploring the late-stage modification of peptides to introduce N-terminal nitriles, epoxides and boronic acids. We demonstrate that the incorporation of warheads into retro‑inverso peptidomimetic sequences can greatly increase their inhibitory activity. This new methodology contributes to the vast amount of research into antiviral therapeutics and suggests a facile means of incorporating warheads into proteolytically stable retro-inverso sequences.