High pathogenicity of viruses belonging to the picornavirus like supercluster, particularly the Middle East Respiratory Syndrome Coronavirus (MERS-CoV), Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), and Noroviruses (NV) have imposed a serious threat to public health underscoring the need for the development of effective countermeasures to combat the infections cause by them. The problem is further compounded by the current lack of approved antivirals for the prevention and treatment of Middle East Respiratory Syndrome (MERS), Coronavirus Disease 2019 (COVID-19) as well as Noroviral Acute Gastroenteritis (AGE). Both coronaviruses and noroviruses encode respective 3C-like protease; an essential enzyme that lies in the heart of the viral replication process. consequently, inhibition of this enzyme is a fruitful avenue of investigation that may lead to the emergence of anti-coronavirus and anti-norovirus therapeutics. This dissertation describes the structure-guided optimization of novel series of dipeptidyl transition state inhibitors of coronavirus 3CL protease and norovirus 3CL protease using X-ray crystallography, iterative medicinal chemistry, enzyme assays, and cell-based replicon system studies. The optimization strategies were chiefly targeted on improving the potency and the metabolic stability of inhibitors that would affirm their therapeutic efficacy. Also, based on the notion that the S4 subsite of the referred protease may provide an effective means of designing potent and cell-permeable inhibitors, indeed validated by demonstrating the proof-of-concept efficacy of a lead compound identified by the aforementioned optimization plan. In the mouse model of MERS-CoV infection, administration of the said lead compound one day after virus infection resulted in 100% survival compared to the 0% survival of the control group of mice.