The novel coronavirus SARS-CoV-2 has recently emerged as a human pathogen in China’s Hubei province, causing severe respiratory illness and pneumonia. According to the World Health Organization (WHO) on March 17th, 2020, there have been over 180,000 cases globally, leading to at least 7,500 deaths. The development of a vaccine will take at least one/two year(s) and the production of a sufficient number of vaccinal doses to protect the world population will represent a big industrial challenge. Thus, there is an urgent need to develop antivirals targeting SARS-CoV-2 and relatives. The objective of the project is to generate nanobinders (nanobodies/VHH and highly stable artificial proteins called aREP) targeting the spike and able to neutralize SARS-CoV-2 in vitro and protect from an infection in an animal infection model. For this goal, we will specifically target its receptor binding domain (RBD) that is known to induce high-titer neutralizing antibodies in others coronaviruses and to fold independently from other spike domains. Neutralizing nanobodies/VHH will be generated after alpaca immunization with the SARS-CoV-2 RBD and neutralizing aREP will be isolated from several independent libraries. Next, biological properties of the VHH and aREP will be characterized (neutralization activity, binding affinity to the (highly glycosylated) spike, thermo-stability, resistance to trypsin and to other proteases present in the lung) and sequence-optimized (VHH sequence humanization, construction of VHH-Fc and aREP-Fc to functionalize them for the immune system,…). Several highly potent candidates will be selected to analyze their prophylactic and therapeutic efficacies (through the intranasal route) in a transgenic mice infection model. Thus, we expect that this general approach targeting the spike RBS will allow the obtention of antivirals or hits for antivirals able to inhibit or block SARS-CoV-2 multiplication in the lung.