The COVID-19 pandemic, produced by a positive-strand RNA virus SARS-CoV-2, has expanded throughout the world and continues for more than three years. To date, more than 30 vaccines have been approved and clinically used in the world to prevent SARS-CoV-2 infection and COVID-19 aggravation. In addition, several drugs have been developed and authorized including Remdesivir, a repositioning inhibitor of RNA-dependent RNA polymerase (RdRp) from Ebola hemorrhagic fever, Molnupiravir, a SARS-CoV-2 RdRp targeting inhibitor, and Nirmatrelvir and Ensitrelvir, SARS-CoV-2 main protease (Mpro) inhibitors (Figure). Development of novel drugs and an increase in the repertory of the drugs are urgently needed. In order to meet this challenge, we have also tried to develop antiviral agents against SARS-CoV-2. In the past three decades, we have been developing anti-HIV-1 agents including entry/fusion, protease, integrase and matrix/capsid degradation/formation inhibitors. According to the classification of viruses, HIV-1 and SARS-CoV-2 belong to positive-sense single-stranded RNA viruses and have some common characteristics. Therefore, we envisioned to apply our obtained knowledge and achievements in the researches on HIV/AIDS to the development of novel SARS-CoV-2 Mpro inhibitors. Initially, we used an active lead compound YH-53/5h, which was developed originally as a SARS-CoV Mpro inhibitor by Hayashi et al. Our strategy was based not only on introduction of fluorine atoms into the inhibitor molecule for increase of binding affinity for the pocket of Mpro and cell membrane permeability but also on replacement of the digestible amide bond by a surrogate structure to increase the biostability of the compounds. Potent and biostable inhibitors of SARS-CoV-2 Mpro were designed and synthesized. The current best compound shows much higher potency than Nirmatrelvir and Ensitrelvir. I would also like to introduce newly designed fusion inhibitors, which have been inspired from our HIV/AIDS researches.