Sub-stoichiometric Modulation of Viral Targets─Potent Antiviral Agents That Exploit Target Vulnerability

Abstract

The modulation of oligomeric viral targets at substoichiometric ratios of drug to target has been advocated for its efficacy and potency, but there are only a limited number of documented examples. In this Viewpoint, we summarize the invention of the HIV-1 maturation inhibitor fipravirimat and discuss the emerging details around the mode of action of this class of drug that reflects inhibition of a protein composed of 1,300− 1,600 monomers that interact in a cooperative fashion. Similarly, the HCV NS5A inhibitor daclatasvir has been shown to act in a highly sub-stoichiometric fashion, inhibiting viral replication at concentrations that are ∼23,500 lower than that of the protein target.

Selected Plant Triterpenoids and Their Derivatives as Antiviral Agents

“…A comparison of basic anti-HIV-1 activity values is shown in Table 4. An overall summary of antiviral activity values of compounds 17-17s, 18, and 19 is presented in Table 5 [46][47][48]. Structurally similar compounds to those mentioned above [46][47][48] were reported recently as second-generation maturation inhibitors (compounds 20-22 and 23a-23e; Figure 4), displaying effect higher than bevirimat (3) against HIV-1 subtype C [49].…”

“…Compounds 18 and 19 had the most desirable overall profile in this series and were evaluated in rat and dog pharmacokinetic studies [47,48]. A comparison of basic anti-HIV-1 activity values is shown in Table 4.…”

“…A comparison of basic anti-HIV-1 activity values is shown in Table 4. An overall summary of antiviral activity values of compounds 17-17s, 18, and 19 is presented in Table 5 [46][47][48]. The investigation of the structure-activity relationships of a series of HIV-1 maturation inhibitors based on the compound 17s (Figure 3) continued by the subsequent incorporation of novel C-17 amine substituents to reduce the overall basicity of the target compounds [47].…”

“…An overall summary of antiviral activity values of compounds 17-17s, 18, and 19 is presented in Table 5 [46][47][48]. Structurally similar compounds to those mentioned above [46][47][48] were reported recently as second-generation maturation inhibitors (compounds 20-22 and 23a-23e; Figure 4), displaying effect higher than bevirimat (3) against HIV-1 subtype C [49]. In silico studies on the interaction of bevirimat and their analogs have been limited to HIV-1 subtype B (5I4T) due to the lack of an available 3D structure for HIV-1 subtype C virus.…”

Celebrating the 60th Anniversary of the MIKIW Meeting-in-Miniature: Virtual Special Issue

“…Finally, in this Virtual Special Issue, you will find several diverse sets of Viewpoints and Perspectives, including a comprehensive analysis of FDA-approved drugs for cancer chemotherapy that function through DNA adducts; a Perspective on the development of peptide–drug conjugates as emerging therapeutic modalities; a Perspective highlighting Gram-negative bacteria drug design, the multifaceted approaches being employed, and current gaps in knowledge for compound development; a personal perspective from one of the early student trainees of the MIKIW meeting; and a Viewpoint from recent MIKIW Keynote speaker, Nick Meanwell, describing opportunities for exploiting the concept of target vulnerability through optimizing drug–target interactions with high levels of cooperativity …”