Oligomerization, albumin binding and catabolism of therapeutic peptides in the subcutaneous compartment: an investigation on lipidated GLP-1 analogs

Peptide therapeutics has made tremendous progress in the past decade. Many of the inherent weaknesses of peptides which hampered their development as therapeutics are now more or less effectively tackled with recent scientific and technological advancements in integrated drug discovery settings. These include recent developments in synthetic organic chemistry, high-throughput recombinant production strategies, highresolution analytical methods, high-throughput screening options, ingenious drug delivery strategies and novel formulation preparations. Here, we will briefly describe the key methodologies and strategies used in the therapeutic peptide development processes with selected examples of the most recent developments in the field. The aim of this review is to highlight the viable options a medicinal chemist may consider in order to improve a specific pharmacological property of interest in a peptide lead entity and thereby rationally assess the therapeutic potential this class of molecules possesses while they are traditionally (and incorrectly) considered ‘undruggable’.

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Recent Advances and Computational Approaches in Peptide Drug Discovery

Current Pharmaceutical Design ◽

10.2174/1381612825666190911161106 ◽

2019 ◽

Vol 25 (31) ◽

pp. 3358-3366 ◽

Cited By ~ 2

Author(s):

Neha S. Maurya ◽

Sandeep Kushwaha ◽

Ashutosh Mani

Keyword(s):

Docking Studies ◽

Computational Approaches ◽

Simulation Tools ◽

Drug Candidates ◽

Recent Advances ◽

Long Duration ◽

Stability Of Complexes ◽

Therapeutic Peptides ◽

Target Binding ◽

Druggable Targets

Background: Drug design and development is a vast field that requires huge investment along with a long duration for providing approval to suitable drug candidates. With the advancement in the field of genomics, the information about druggable targets is being updated at a fast rate which is helpful in finding a cure for various diseases. Methods: There are certain biochemicals as well as physiological advantages of using peptide-based therapeutics. Additionally, the limitations of peptide-based drugs can be overcome by modulating the properties of peptide molecules through various biomolecular engineering techniques. Recent advances in computational approaches have been helpful in studying the effect of peptide drugs on the biomolecular targets. Receptor – ligand-based molecular docking studies have made it easy to screen compatible inhibitors against a target.Furthermore, there are simulation tools available to evaluate stability of complexes at the molecular level. Machine learning methods have added a new edge by enabling accurate prediction of therapeutic peptides. Results: Peptide-based drugs are expected to take over many popular drugs in the near future due to their biosafety, lower off-target binding chances and multifunctional properties. Conclusion: This article summarises the latest developments in the field of peptide-based therapeutics related to their usage, tools, and databases.

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Recent Advances on Therapeutic Peptides for Breast Cancer Treatment

Current Protein and Peptide Science ◽

10.2174/1389203721999201117123616 ◽

2020 ◽

Vol 21 ◽

Author(s):

Samad Beheshtirouy ◽

Farhad Mirzaei ◽

Shirin Eyvazi ◽

Vahideh Tarhriz

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Tumor Cells ◽

Breast Cancer Cells ◽

Specific Binding ◽

High Specificity ◽

The Novel ◽

Anti Cancer ◽

Therapeutic Peptides ◽

Low Toxicity

: Breast cancer is a heterogeneous malignancy which is the second cause of mortality among women in the world. Increasing the resistance to anti-cancer drugs in breast cancer cells persuades researchers to search the novel therapies approaches for the treatment of the malignancy. Among the novel methods, therapeutic peptides which target and disrupt tumor cells have been of great interest. Therapeutic peptides are short amino acids monomer chains with high specificity to bind and modulate a protein interaction of interest. Several advantages of peptides such as specific binding on tumor cells surface, low molecular weight and low toxicity on normal cells make the peptides as an appealing therapeutic agents against solid tumors, particularly breast cancer. Also, National Institutes of Health (NIH) describes therapeutic peptides as suitable candidate for the treatment of drug-resistant breast cancer. In this review, we attempt to review the different therapeutic peptides against breast cancer cells which can be used in treatment and diagnosis of the malignancy. Meanwhile, we presented an overview of peptide vaccines which have been developed for the treatment of breast cancer.

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Comparative Preclinical Evaluation of HER2-Targeting ABD-Fused Affibody® Molecules 177Lu-ABY-271 and 177Lu-ABY-027: Impact of DOTA Position on ABD Domain

Pharmaceutics ◽

10.3390/pharmaceutics13060839 ◽

2021 ◽

Vol 13 (6) ◽

pp. 839

Author(s):

Yongsheng Liu ◽

Anzhelika Vorobyeva ◽

Tianqi Xu ◽

Anna Orlova ◽

Annika Loftenius ◽

...

Keyword(s):

A Priori ◽

Albumin Binding ◽

Tumor Uptake ◽

Site Specific ◽

Affibody Molecules ◽

Preclinical Evaluation ◽

Renal Uptake ◽

C Terminus ◽

Minimal Modification ◽

Structure Properties

Radiolabeled Affibody-based targeting agent 177Lu-ABY-027, a fusion of an anti-HER2 Affibody molecule with albumin binding domain (ABD) site-specifically labeled at the C-terminus, has demonstrated a promising biodistribution profile in mice; binding of the construct to albumin prevents glomerular filtration and significantly reduces renal uptake. In this study, we tested the hypothesis that site-specific positioning of the chelator at helix 1 of ABD, at a maximum distance from the albumin binding site, would further increase the strength of binding to albumin and decrease the renal uptake. The new construct, ABY-271 with DOTA conjugated at the back of ABD, has been labelled with 177Lu. Targeting properties of 177Lu-ABY-271 and 177Lu-ABY-027 were compared directly. 177Lu-ABY-271 specifically accumulated in SKOV-3 xenografts in mice. The tumor uptake of 177Lu-ABY-271 exceeded uptake in any other organ 24 h and later after injection. However, the renal uptake of 177Lu-ABY-271 was two-fold higher than the uptake of 177Lu-ABY-027. Thus, the placement of chelator on helix 1 of ABD does not provide desirable reduction of renal uptake. To conclude, minimal modification of the design of Affibody molecules has a strong effect on biodistribution, which cannot be predicted a priori. This necessitates extensive structure-properties relationship studies to find an optimal design of Affibody-based targeting agents for therapy.

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