CTSLCTSB-IN-1 (compound 212-148) is a bispecific inhibitor of host viral spike cleaver proteins CTSL/CTSB and TMPRSS2 with IC 50 s of 2.13/64.07 nM and 1.38 μM, respectively. CTSLCTSB-IN-1 blocks two relevant SARS-CoV-2 viral entry pathways by inhibiting the viral spike cleavage and can be applied to anti-SARS-CoV-2 research.