There is considerable scientific evidence for the need for vaccines and antiviral drugs as viruses remain a major cause of disease today. There are increasing reports and data to show that viruses are mutating and reemerging. This re-emergence can prove more costly if vaccines fail to work on these mutated viruses. Mutations are typically an evolutionary adjustment by viruses to escape therapeutic molecules (chemical entities) and potentially re-emerge as a pandemic. In case of SARS-CoV-2, there is an urgent need to understand how vaccines or drugs might be impacted by such reported mutations.
Even though the use of antiviral peptides is still low, their potential of such peptides is well understood. Such peptides can be synthetic or may originate from natural sources.
First-generation new chemical entity-based antivirals from the early 70s had several side effects on humans due to poor specificity. For example, vidarabine, a replication inhibitor, is also a eukaryotic analog. Second-generation molecules became more specific and lower in toxicity. However, with the emergence of drug resistance and the low efficacy of these antivirals, viral infections are resurfacing across the globe, as can be seen in cases such as H1N1, Ebola and Zika virus (ZIKV).
This suggests that there is a need for the development of new antiviral drugs which can overcome resistance and also act as a defensive barrier. It is in this context that antiviral peptides (AVPs) have become a hot topic of discussion during the SARS-CoV-2 (COVID-19) pandemic.
Peptides as biologics
COVID-19 has thrust the whole world into an uncertain future. Due to its high rate of human-to-human transmission and mortality rates, it has become crucial to develop more than one way of tackling this infection. In this disease, the S1 subunit of the spike protein interacts with the human angiotensin-converting enzyme (hACE2) receptor for entry into the cell. Once inside the host cell through the entry points of nose and mouth, it rapidly migrates to the lungs, the brain and the intestine, where there is an abundance of hACE2. Post-infection, the host’s innate immunity is impaired, resulting in illness. Higher rates of illness and mortality are strongly associated with the aged and patients with already weakened immune systems and comorbidities such as diabetes, hypertension, cancer, lung disease and obesity.
To date, there are no clinically approved drugs or vaccines to prevent or treat this infection. The initial moves to repurpose drugs such as hydroxychloroquine, chloroquine, remdesivir, lopinavir etc. have met with limited success and have revealed several side-effects. Therefore, there is an urgent need for alternate antiviral agents and therapies to stop the spread of this virus. Crystal structures of the viral proteins have been published and several scientific groups have been working on developing peptide-based drugs. On February 21, 2020, the US FDA updated its definition of a biologic to include synthesized polypeptides which have amino acids between 40-100 (synthetic proteins) and synthetic peptides below 40 amino acids. This reclassification has helped pharma companies to focus on and develop novel peptides with antiviral activity.
Peptides were previously not considered for drug development as they readily degraded within the human body. However, with the onset of novel methods of peptide modification to achieve a sustained functional activity, many pharmaceutical companies have come forward with potential treatments. Several peptides approved by FDA are synthetic in nature and cover a wide range of conditions such as cancer, infection, metabolic diseases, haematology and cardiovascular diseases.
As peptides offer greater efficacy, safety and tolerability in humans compared to small molecules, as well as reduced chances of inducing mutations, they may be the much-needed solution to the present pandemic.
Due to properties such as greater ease of penetrating cell membranes thanks to their smaller size, peptides are better drugs compared to proteins.
Currently, out of the more than 400 drugs in development worldwide for the treatment of COVID-19,at least 22 are peptide drugs at different stages of development. There are five synthetic peptide candidates being tested in patients: Four are in phase II (Plitidepsin – Pharma Mar SA, Aviptadil – Relief Therapeutics Holding AG, Solnatide – Apeptico Forshung und Entwicklung GmBH and Metenkefalin – Cytocom Inc). Ampio Pharmaceuticals Inc has filed IND/CTA (US) for Ampion peptide. A phase I trial has been started for PUL-042 by Pulmotect Inc. Several preclinical trials are in motion by F4 pharma GmBH (FX-06), NovaCell Technology Inc (NCP-112) and Apellis Pharmaceuticals Inc (APL-9). The companies at the discovery stage are Neuome Technologies Pvt. Ltd. (Pep4/D), Santhera Pharmaceuticals (lonodelestat), Kalos Therapeutics Inc (KTH-222), BioMarck Pharmaceuticals (BIO-11006), InterK Peptide Therapeutics Ltd, Lingandal Inc and Immupharma Plc. Neuome Technologies, based in India, is also working on developing peptide-based drugs with multipotency.
The most promising peptides are looking not just for viral load reduction, but also at several other aspects such as a reduction of alveolar oedema and thrombosis formation in the lungs. Several studies have indicated that the increase in mortality rates seen in COVID-19 is due to pulmonary thrombosis, while increased levels of D-dimer and fibrinogen have also been observed. Therefore, peptide-based drug development must focus not only on prevention of viral infection but also multiple other functions.