We recently identified a new class of cyclic peptide triazoles that can irreversibly inactivate the HIV-1 envelope (Env) trimer on virus and Env-expressing cells. Linear peptide triazoles (PTs) were previously identified that inactivate HIV-1 Env by binding to the conserved CD4 binding epitope on Env-gp120. PT binding leads to inhibition of further conformational changes in the Env to achieve co-receptor binding and therefore halts the entry process. The irreversible inactivation process occurs as a result of efficient gp120 shedding of the virions upon binding to PTs, leaving only gp41-coated virions that are no longer infectious. Through side chain-to-side chain cyclization and chemical modifications including on-resin C-C coupling, we generated a class of cyclic peptide triazoles (cPTs) that, in addition to retaining all phenotypes of the linear peptides, massively resist proteolytic degradation and show promising in vivo half-life of ~ 3 h in rats. Both linear and cyclic peptide triazoles also bind to envelope on infected cells and cause gp120 shedding similar to that observed with the virions, suppressing the formation of new infectious viruses from infected cells. Selective killing of HIV-1 infected cells has been successfully demonstrated by multivalent linear PTs. Recapitulating this Env-targeting inactivation with the more advanced cPTs, and combining Env with strategies for infected cell activation and Env expression, offer the potential to use the cPT class of inhibitors in HIV CURE development.