You Cannot Have Your Synergy and Efficacy Too

Abstract

models for both the GABA A receptor and 11b-hydroxylase when performing their docking studies. Nevertheless, they were still able to successfully identify compounds that were potent GABA A receptor modulators but lacked significant 11b-hydroxylase inhibitory activity. Recently, Laverty et al. reported the structure of a synaptic GABA A receptor using cryo-electron microscopy [10]. Thus, one could reasonably expect that in silico screening assays utilizing this new structure could provide even more accurate predictions of GABA A receptor modulatory potency and anesthetic activity. In summary, there is a compelling need for new general anesthetics that are devoid of the side effects that risk harm to patients. The work by Cayla and colleagues provides proof-ofconcept for the use of in silico docking approaches to rapidly screen virtual libraries to identify compounds with potent anesthetic activities that are devoid of side effects mediated by off-target sites. We look forward to the day when a novel anesthetic agent first identified by such approaches is available for use in patients.

Early exposure to broadly neutralizing antibodies may trigger a dynamical switch from progressive disease to lasting control of SHIV infection

“…Administered bNAbs are assumed to induce a net enhancement of the viral clearance rate by a time-dependent amount, A , which is a saturable function of the instantaneous serum concentration of the two bNAbs, 3BNC117 ( A 1 ) and 10-1074 ( A 2 ). The functional form mimics the 2D Hill equation derived recently to describe the effect of drug combinations [ 56 , 57 ] and has been used to quantify combinations of Abs and virus entry inhibitors [ 57 , 58 ], expected to be similar to the combination of bNAbs targeting non-overlapping sites on the HIV-1 envelope used here [ 10 ]. The net enhancement of viral clearance combines the direct effect on viral clearance by bNAbs [ 22 ] as well as the reduction in infectivity, β , due to viral neutralization by the bNAbs [ 59 ].…”

Targeting TMPRSS2 and Cathepsin B/L together may be synergistic against SARS-CoV-2 infection

“…The two are equivalent ways of quantifying synergy. The latter has been termed Bliss synergy and is more widely used [43,[50][51][52]. Here, we employed the latter measure throughout and denoted it as…”

Targeting TMPRSS2 and Cathepsin B/L Together May Be Synergistic Against SARS-CoV-2 Infection

“…The synergy we elucidated is unconventional and arises because two independent entry pathways are accessible to SARS-CoV-2. Classically, synergy is thought to arise between drugs when one of the drugs potentiates the other through interactions between their targets or downstream pathways (Fitzgerald et al, 2006;Foucquier and Guedj, 2015;Meyer et al, 2020Meyer et al, , 2019Sen et al, 2019). No such interaction is evident here.…”

“…The trade-off implies that as the efficacy of a combination increases beyond a point, the synergy decreases, thereby limiting the synergy that can be realized given a desired efficacy. This trade-off originates from the classical drug interactions underlying synergy, where, for instance, one drug potentiates the other in blocking different steps of the same pathway (Sen et al, 2019). If one of the drugs is used at such high efficacies that the pathway is nearly completely blocked, then little room is left for the other drug to act and no synergy is possible.…”

“…The two are equivalent ways of quantifying synergy. The latter has been termed Bliss synergy and is more widely used (Foucquier and Guedj, 2015;Jilek et al, 2012;Meyer et al, 2019;Sen et al, 2019). Here, we employed the latter measure throughout and denoted it as…”