Targeted Biologics: The New Frontier for Precision Therapy

Functionalized antibodies, protein subs titution, supplementation therapies, and enzyme-based therapeutics are protein-based approaches for the treatment and cure of human genetic and acquired diseases. Gene editing and RNA-based therapeutics, including siR NAs, microRNAs, and antisense oligonuc leotides (ASOs), target the ma- chinery that produces disease-associat ed proteins. Protein-based and RNA-based products are collectively referred to as biologics. This Thematic Issue opens a novel specialized s ection of Current Medicinal Chemistry focused on targeted biologics at various stages of discovery, preclinical and clinical development. We hope it might encourage the advancement of this field by stimulating researchers to share their results. Within this issue, readers will find papers discussing th e use of replacement proteins therapeutics, with two ex- amples provided. Alpha-1-antitrypsin and C-1 inhibitor (or C1-esterase inhibitor) both belong to the family of ser- pins and are indicated for the treatment of conditions that result from pat hologically low levels or non-functional variants. Alpha-1-antitrypsin is a small protein that inhib its the catalytic action of el astase, a proteolytic enzyme. When the action of elastase is not properly counterbalan ced by alpha-1-antitrypsin in the lung, pulmonary emphy- sema develops. Alpha-1-antitrypsin was approved more than thirty years ago and is used for the treatment of Alpha- 1-antitrypsin deficiency. The paper by Bianchera et al. [1] reports on issues associated with alpha-1-antitrypsin pro- duction from either animal sources or heterologous expre ssion, focusing on existing and novel protein formulations and delivery strategies. The C-1 inhibitor is involved in a re gulatory network of comple ment, contact, coagulation, fibrinolytic systems and functions as an anti-inflammatory agent in circulation. C-1 inhibitor is used as a prophylactic or acute treatment in Hereditary Angioedema (HAE), which is a rare genetic disease. The paper by Karnaukhova et al. [4] provides an overview of the biochemical properties of C-1 inhibitor, its role in HAE, recent progress in therapeutic strategies for this disease treatment, as well as potential applications fo r sepsis, endotoxin shock, antibody-mediated rejection fol- lowing kidney transplantation, and severe systemic abnormalities related to COVID-19. During the Vietnam War in the late 1960s, the United States started searching for blood substitutes, such as mod- ified hemoglobin or perfluorocarbon solutions, to replace transfusions when blood was unavailable. Since then, many attempts have been carried out, including the devel opment of chemically and/or genetically modified hemo- globins designed to mimic red blood cells. The paper by Sakai et al. [7] summarizes the intense activities carried out predominantly in Japan towards th e development of hemoglobi n-containing liposomes. Issues associated with lipids purity, hemoglobin purification, and stability towards oxidation are presented and discussed. There are many pathophysiologic aberrati ons associated with genetic variants of hemoglobin, often caused by single amino acid substitutions. One such example is the single amino acid Glu-Val substitution at position 6 of the beta chains, leading to sickle cell disease. Hydroxyurea is a mainstay of sickle cell disease therapy to increase the percentage of fetal hemoglobin. Novel marketed therap eutics are based on compounds either interacting directly with hemoglobin to modulate oxygen binding or altering water-controlling pump systems. Alternative and more recently proposed approaches are based on hematopoietic st em cell transplantation and gene therapy platforms. These approaches are reviewed by Garg et al. [3] which discuss advances in