The current COVID-19 pandemic is an unprecedented health and economic emergency. COVID-19 is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has already caused more than 1 million deaths all over the world and the death toll increasing at an alarming rate. Several clinical trials are underway to test vaccines and available antiviral drugs, but no effective therapy has emerged yet. What is more, the virus has acquired a number of mutations that might make it more infectious and cause resistance to antiviral drugs and thus require a combined therapy targeting different viral genes.

Since the beginning of the pandemic, my group has used large-scale computer simulations and free energy calculations combined with experiments to address various relevant questions and design new drugs. In particular, we studied the effects of the prevalent genetic variants on the conformational changes of the spike of COVID-19 to understand their effect on infectiousness.¹  We are also using computer aided drug discovery approaches to design new peptides that block the spike-receptor interactions and small molecules that bind non-structural protein 1, an important yet difficult-to-target viral protein.

Finally, we are supporting clinical research in the repurposing of anticancer drugs that have been shown to be effective in blocking the virus entry in human cells.

^1. Ilmjärv, S; Abdul, F; Acosta-Gutiérrez, S; Estarellas, C; Galdadas, I; Casimir, M; Alessandrini, M; Gervasio, FL; Krause, KH. Epidemiologically most successful SARS-CoV-2 variant: concurrent mutations in RNA-dependent RNA polymerase and spike protein doi: https://doi.org/10.1101/2020.08.23.20180281

According to Wikipedia, a cascade reaction is a chemical process that comprises of at least two consecutive reactions such that each subsequent reaction occurs only in virtue of the chemical functionality formed in the previous step. In cascade reactions, isolation of intermediates is not required, as each reaction in the sequence occurs spontaneously. Strictly speaking, the reaction conditions do not change during the consecutive steps of a cascade and no new reagents are added after the initial step. In contrast, one-pot procedures similarly allow at least two reactions to be carried out consecutively without any isolation of intermediates, but do not preclude the addition of new reagents or the variation in conditions after the first reaction. Thus, any cascade reaction is also a one-pot procedure, while the reverse is not the case.

The main benefits of one pot sequences include high atom economy and reduction of waste generated by the several chemical processes, as well as of the time and effort required to carry them out.

Since the first example of the Tropinone synthesis by Robinson in 1917, the use of cascade reactions has proliferated in the area of total synthesis.

This kind of step economic strategy was applied in our laboratory to the shortening of the synthetic pathways for well-known olfactive ingredients, such as the green galbanum-like “Galbanolene”, the sandalwood-like Firsantol® and natural “(-)-(Z)-ß-Santalol”, the floral Hedione® or jasmine-like “Methyl Jasmonate”, the musky macrocyclic “Muscone”, and the amber-like tricyclic Ambrox®. All these examples shall be presented chronologically with respect to a typical industrial career at Firmenich.