Given its pivotal role in the viral life cycle, blocking integrase (IN) through IN strand transfer inhibitors (INSTIs) represented a breakthrough in the treatment of HIV infection, establishing these antiretroviral regimens as first‐line options against AIDS. However, the onset of drug‐resistant strains has challenged the efficacy of INSTIs, demanding new efforts in the search for therapeutic tools that work through alternative modes of action. In this context, the discovery of allosteric IN inhibitors (ALLINIs) has highlighted new opportunities to target IN beyond its active site, enhancing antiviral efficacy and the genetic barrier to resistance. Extensive drug discovery campaigns have resulted in the development of effective ALLINIs with both in vitro and in vivo efficacy, two of which are advancing in clinical trials as next‐generation therapeutic tools. Nevertheless, advancements in structural biology have critically aided in elucidating the underlying effects of ALLINIs, highlighting a complex, multimodal mode of action that ultimately yields defects in virion maturation. This review focuses on ALLINIs, providing a comprehensive overview of major drug discovery efforts devoted to this field, with an emphasis on the medicinal chemistry and structural biology findings that have revealed unprecedented opportunities for developing innovative and effective anti‐HIV drugs.
Francesco Saccoliti, E. Patacchini, Emanuele Cara et al.· ChemMedChem· 0 citations
The SARS-CoV-2 pandemic has posed a tremendous burden globally, highlighting the urgent need for new effective antivirals that are possibly useful against future emerging Coronaviruses (hCoVs). In this context, major efforts were focused on the inhibition of highly conserved and essential targets playing a pivotal role in viral replication. Among them, SARS-CoV-2 nsp13 stands out, being the most conserved enzyme within hCoVs. Following our previous reports describing the identification of indole-based diketo acid (DKA) derivatives as SARS-CoV-2 nsp13 inhibitors endowed with antiviral activity, we applied a scaffold hopping strategy to identify new nsp13 inhibitors. Therefore, we investigated a series of 4-phenyl pyrrolyl DKAs and their structural analogs characterized by molecular simplification or DKA isosteric replacement. The derivatives showed potency against both nsp13-associated activities exhibiting measurable IC50s in the low micromolar/submicromolar range, highlighting a promising dual inhibitory profile accordingly. Structure–activity relationship (SAR) studies were performed, highlighting the main structural features increasing the activity of the different compound classes. Interestingly, SAR trends were confirmed in the presence of the BSA/TCEP system despite variations in potency. To shed light on the interaction of the best acting compounds 13b, 15a, and 17d, docking studies were performed, suggesting a putative binding mode in agreement with our previous findings.
E. Patacchini, Francesco Saccoliti, Roberta Emmolo et al.· Molecules· 0 citations
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still a major public health issue, even today. Among the SARS-CoV-2 nonstructural proteins, the main protease (Mpro) plays a critical role in viral polyprotein processing and is therefore indispensable for viral replication. For this reason, it represents one of the most promising therapeutic targets for the development of antiviral agents against SARS-CoV-2. Currently, only one protease antiviral agent (nirmatrelvir) has received emergency approval for COVID-19 treatment, the disease caused by SARS-CoV-2 infection. However, the emergence of viral mutations may compromise its efficacy, highlighting the urgent need to develop new, safe, and effective protease antiviral agents. In the present work, we designed and synthesized new SARS-CoV-2 Mpro small-molecule inhibitors endowed with a pyrimidine scaffold. A series of derivatives were evaluated in both biochemical and cell-based assays to assess their antiviral efficacy, with some of them being able to inhibit the SARS-CoV-2 Mpro activity and to suppress viral replication. Docking studies were confirmed by site-directed mutagenesis, and the mechanism of action of the most promising compound was elucidated.
Salvatore Nieddu, Giuseppe Ruggieri, Riccardo De Santis et al.· ACS Infectious Diseases· 0 citations
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