Cryptophycin Synthesis Essay

In the previous section we have discussed how various programs for drug development using natural products evolved at NIH. The NCI DTP model paved the way for the NCDDGs, which in turn provided the structural basis for the ICBGs administered by FIC. Thus, the principles enumerated in the NCI DTP's LOC and MOU, provide the fundamental framework for international cooperation in all NIH Programs for drug development using natural products. The standard LOU and MOU are available at the websites provided in Table 1.

When dealing with traditional knowledge and genetic resources, it is to be noted that these assets cannot be assessed by the same criteria as those applied for other kinds of assets. For example, traditional knowledge generally belongs to a community and therefore, lies in the public domain. Hence, it does not meet the standard criteria of novelty, utility and non-obviousness, as applied to inventions by the U.S. Patent law, and does not warrant intellectual property protection. Also, while most western countries share similar patent laws that define inventorship, there are specific differences in the laws from one country to another and they are applicable only within the boundaries of each country. Moreover, there are specific patent laws pertaining to plant material, which can vary considerably between nations [21]. Hence, in international collaborations involving traditional knowledge and/or genetic resources, structured benefit-sharing agreements negotiated upfront may help to transcend national barriers and assist cooperating parties to reach clearly defined common understanding. Agreements may incorporate plans for benefit sharing in the form of royalties (upfront royalties and/or royalties decided only after product shows promise), milestone payments and intangible gains of capacity building via local training and infrastructure development. For NIH, the NCI LOC and MOU have helped to address these issues and to establish some ground rules while embarking on such collaborations.

NCI LOC and MOU

The LOC and the MOU developed at NCI recognize the value of the natural resources (plant, marine, microbial) being investigated by the NCI researchers, and the significant contributions being made by the source country (SC), source country government (SCG), or source country organization (SCO) in aiding the NCI collection programs. Hence, these agreements attempt to balance the interests of the indigenous peoples, SC and SCO, with those of the U.S. Government and private sectors. Several policies, aimed at facilitating collaboration with and compensation of countries participating in the NCI drug discovery program, have been developed. These policies, which were initially outlined in the NCI/DTP Letter of Intent (LOI) [2], have later been implemented through the LOC and MOU. They are also included in the form of public policy or public benefit obligations (so called “White Knight” clauses) in licensing agreements developed at the NIH Office of Technology Transfer (OTT).

It must be mentioned at the onset that the NCI LOC and MOU are not mechanisms for licensing IP Rights (IPR) in cooperative research funded by the U.S. Government. Such rights can only be delineated in a CRADA by U.S. law [discussed in detail in Ref. 2]. Generally, a CRADA is only negotiated at a stage of research when there is a defined invention that needs further development with the assistance of a commercial partner. The policy of NIH is to defer negotiations regarding licensing of IPR and specific royalty rates until a specific invention is identified. Therefore, at early stages of drug discovery involving natural products, when the results are uncertain, no commitments regarding IP (involving patenting or licensing) can be made by NIH, an Agency of the U.S. Government. However, these same internal policies dictate NCI to “make best effort” (a phrase of specific significance in U.S. law, implying strong commitment) in providing opportunities to its collaborating partners for continuous engagement in the drug discovery process and fair and equitable compensation, where applicable.

For example, NCI/DTP policy dictates that if drug is commercialized, the SCO is appropriately compensated. As stated in Article 8 of the LOC, “Should an agent derived from an organism collected under the terms of this agreement eventually be licensed to a pharmaceutical company for production and marketing, DTP/NCI, will request that NIH/OTT require the successful licensee to negotiate and enter into agreement(s) with appropriate [SCG] agency(ies) or [SCO] within twelve (12) months from the execution of said license. This agreement(s) will address the concern on the part of the [SCG or SCO] that pertinent agencies, institutions and/or persons receive royalties and other forms of compensation, as appropriate.” The above benefits are provided regardless of whether the development is for a direct isolate or synthetic material derivative. As stated in Article 9 of LOC - “The terms of Article 8 shall apply equally to inventions directed to a direct isolate from a natural product material, a product structurally based upon an isolate from the natural product material, a synthetic material for which the natural product material provided a key development lead, or a method of synthesis or use of any aforementioned isolate, product or material; though the percentage of royalties negotiated as payment might vary depending upon the relationship of the marketed drug to the originally isolated product. It is understood that the eventual development of a drug to the stage of marketing is a long term process which may require 10-15 years.”

Also, collection contractors must collaborate with SCO through the duration of the project. To ensure continued involvement of the SC/SCO, the drug developer must use the SC as first source of bulk natural product supply if possible. According to Article 10 of LOC, “In obtaining licensees, the DTP/NCI/NIH will require the license applicant to seek as its first source of supply the natural products from [Source Country]. If no appropriate licensee is found that will use natural products available from [Source Country], or if the [SCG] or [SCO] as appropriate, or its suppliers cannot provide adequate amounts of raw materials at a mutually agreeable fair price, the licensee will be required to pay the [SCG] or [SCO] as appropriate, compensation (to be negotiated) to be used for expenses associated with cultivation of medicinal organisms that are endangered, or for other appropriate conservation measures. These terms will also apply in the event that the licensee begins to market a synthetic material for which a material from [Source Country] provided a key development lead.”

With the increasing awareness of the value of indigenous genetic resources, many countries now prefer to carry out initial research in the home country. For this reason, NCI now favors the use of the MOU with collaborating SCOs that are suitably qualified to perform in-country processing rather than using contract collectors and LOC. NCI assists the SCO in establishing a pre-screen and active SCO extracts or compounds are perhaps further screened at NCI. Joint patents are sought on all inventions co-developed under the MOU between SCO and DTP. SCOs can also be sole inventors. As stated in Article 9 of MOU, “Both [SCO] and DTP/NCI recognize that inventorship will be determined under patent law. DTP/NCI/NIH and [SCO] will, as appropriate, jointly seek patent protection on all inventions jointly developed under this MOU by DTP/NCI and [SCO] employees, and will seek appropriate protection abroad, including in [Source Country], if appropriate. Application for patent protection on inventions made by [SCO] employees alone will be the responsibility of [SCO]. Application for patent protection on inventions made by DTP/NCI employees alone will be the responsibility of DTP/NCI.”

When materials are collected under the LOC, NCI/DTP takes the lead in isolating, characterizing, and patenting active agents. However, a major component of NCI/DTP is also to promote development of the agent in the SC. Therefore, capacity building plays an important role in the process. The agreements enable SC scientists to work at NCI as guest researchers whenever possible, and training is provided for SCO scientists. DTP/NCI also provides a number of resources to the SC/SCO free of charge, without claiming contribution toward inventorship in drug development. Some examples include (1) in vitro screening of natural product extracts and compounds, (2) in vivo evaluation of efficacy, and (3) algorithms for possibly identifying anti-tumor compounds with new mechanisms of action. Such “soft benefits” may sometimes be of greater value to the SC/SCO over the long term than financial payments. This is especially true when the research may not eventually lead to any product development due to failure in clinical trials, technical difficulties, etc. According to Article 3 of the LOC, “in the course of the contract period, DTP/NCI will assist the [SCO], thereby assisting [SC], to develop the capacity to undertake drug discovery and development, including capabilities for the screening and isolation of active compounds from plants, micro-organisms and marine organisms.” Similar language is also provided in Article 6 of MOU. The LOC goes further to state: “Subject to the provision that suitable laboratory space and other necessary resources are available, DTP/NCI agrees to invite a senior technician or scientist designated by [SCO] to work in the laboratories of DTP/NCI or, if the parties agree, in laboratories using technology which would be useful in furthering work under this agreement” [Article 4]…. “The DTP/NCI will make a sincere effort to transfer any knowledge, expertise, and technology developed during such collaboration in the discovery and development process to [SCO], subject to the provision of mutually acceptable guarantees for the protection of intellectual property associated with any patented technology” [Article 5]. The above clauses are also iterated in the MOU, in Articles 7 and 10, respectively.

Both the LOC and the MOU also contain elaborate guidelines for the process of data sharing and mutual confidentiality between NCI and SC/SCO, for the purpose of IP protection and technology development. MOUs are generally five-year agreements, while the LOCs have no expiration date. For the benefit of the provider, NCI expresses its desire to adhere to all the terms of the LOC or MOU, even in absence of a formal agreement or when the MOU has expired.

The principles of benefit sharing outlined in the NCDDG and the ICBG utilize the model of NCI DTP and the overarching elements of the NCI LOC/MOU agreements provide a foundation for these extramural programs. As discussed earlier, both NCDDG and ICBG programs are initiated by U.S. investigators outside NIH that receive NIH funding; however, NIH has considerable involvement in these programs to achieve the desired goals and objectives. The guiding principles of benefit sharing agreements for all three programs – NCI/DTP, NCDDG and ICBG – are itemized in Table 4.

Article 15.1 of the CBD recognizes the rights of national governments to regulate access to genetic resources located within their borders. Article 15.5 specifies the requirement of prior informed consent (PIC) from the party that provides access to its genetic resources. Article 8(j) of the CBD recognizes the rights of indigenous and local communities on their traditional knowledge, innovation and practices [22,11]. It is noteworthy that the NCI LOC was drafted in 1988 - 4 years prior to the drafting of the CBD (1992) by the UN. Yet, the LOC (and the MOU, drafted shortly thereafter) contain the same ideals and policies as the CBD regarding equitable benefit sharing between the U.S. and the developing source countries, and for capacity building of SCs with the purpose of technological and economic development. The DTP also paid attention to the ecological value of natural resources and promoted their sustainable use.

The above philosophy and associated policies were also adopted in the ICBG Program, later developed by FIC. Although the U.S. did not become a signatory to the CBD, which was adopted at the “Earth Summit” in Rio de Janeiro in 1992, the underlying principles of the CBD – conservation, sustainable use and equitable benefit sharing -are the same as those of the ICBG program funded through the U.S. Government. The ICBG program attempts to meet the same three goals through research and development in a manner compatible with existing legal frameworks such as the CBD and TRIPS. Operationally, the ICBG program has served to provide a functional model for some countries party to the CBD. Developing countries participating in ICBG have used the mechanism as a testing ground for creating public-private partnerships and developing policies relevant to CBD, such as access and benefit sharing for genetic resources.

Mechanisms Specific to ICBG

The terms and conditions of equitable benefit sharing in ICBG agreements have been published in detail and will not be discussed here [Rosenthal, JP “Equitable Sharing of Biodiversity Benefits: Agreements on Genetic Resources” presented at International Conference on Incentive Measures for the Conservation and Sustainable Use of Biological Diversity, Cairns, Australia, 25-28 March 1996]. However, we highlight below some unique issues and elements of legal mechanisms specifically encountered in agreements within certain ICBG programs, which vary from the DTP mechanisms [17].

I. Royalty Structure

Royalties are usually percentages of the selling price of commercialized products. For all cooperative programs discussed above, monetary compensation in the form of royalties, as negotiated in a contract, depends on the relative contribution of collaborating partners. The valuation of the royalty may depend on the chemical nature of the pharmaceutical product (e.g., the structural relationship between the commercialized drug moiety and the lead compound as originally isolated) or the kinds of assays (functional vs. mechanistic) by which the active principle was detected. For example, a higher royalty is generally obtained if the commercialized product is a direct isolate or very similar to the source natural product rather than a chemically-modified derivative of the original compound or structural moiety found in the extract. In addition to the above, for certain ICBG programs, the timing of the negotiations has also been known to influence royalty structure. Unlike in NCI/DTP, where negotiations regarding licensing of IPR and specific royalty rates are deferred until positive results for natural products are obtained on NCI screens or a specific invention is determined, ICBG benefit-sharing negotiations have been known to occur either before or after positive drug-screening data were conclusively obtained. Usually the SC or SCO negotiates a higher rate of royalty when positive results exist from the screening of extracts. On the other hand, in the absence of screening data, the SC or SCO may still negotiate upfront payments at the onset of collaboration to assure some monetary gain regardless of the outcome. However, the negotiated rates of such upfront royalties are always less because of the uncertainty of the outcome. Hence, this is a low-risk, low-return form of partnership investment for SC/SCO.

II. Know-How Licenses

Compared to genetic resources, even more difficult is the process of valuation and compensation of traditional knowledge that might play an integral part in drug development. Traditional ethno-botanical knowledge may help researchers to identify what part of a plant contains the active medicinal moiety, what times of the year are best for harvesting the material and so on. A given compound may be concentrated in the roots rather than in the aerial systems of a plant and may appear to be synthesized in a particular season or developmental stage of the plant. Traditional ethno-medical knowledge may provide direct association between a natural product (e.g., plant extract) and its use as remedy against a type of disease. Obtaining such indigenous knowledge may greatly expedite the process of drug discovery and reduce the costs in terms of time, labor and utilization of research resources (such as by reducing the number of expensive assays that need to be performed). It can also make drug discovery from natural products cost-effective (1) by efficacious short-listing of pharmacologically-active plants etc., and (2) by providing a specific end use for the product [23]. For example, the anti-HIV moiety found in the bark of Homalanthus nutans, a tree growing in the rain forests of Western Samoa, occurs in one of two varieties and is produced only when the tree is of a certain size. Dr. Paul Alan Cox, an American ethnobotanist, obtained this pertinent information from local Samoans who used this tree bark for centuries for treatment against symptoms of liver diseases resembling those of yellow fever and hepatitis, and this traditional knowledge guided his discovery of prostratin (see Case Study 3).

It is important to remember, however, that because of its existence in the public domain, traditional knowledge is non-patentable. Compensation for such knowledge may be through various forms of agreement structure. One such mechanism is the use of a “know-how license” - a type of industrial agreement that provides the licensee exclusive or non-exclusive rights to utilize the informal knowledge for associated technology development. While not always easy to negotiate due to legal complications, such a mechanism has been used in some ICBG programs to provide financial compensation for the use of such knowledge. A know-how license helps to recognize and protect indigenous knowledge in a manner that is commercially viable and resonant with the procedures of the industries in the developed world.

III. Issues involving Ownership of Genetic Resources and Traditional Knowledge

The ICBG Program requires that near- and long-term benefits be returned to collaborating communities, whether it is solely for the utilization of genetic resources or for both the resources and traditional knowledge associated with such resources. Genetic resources of natural products are generally owned by the SCG or local owners of the land. The CBD recognizes the sovereignty of nations over their genetic resources (Article 15). Hence, these are the benefit-sharing entities of the partnership with respect to resources. However, it is a daunting task to identify who is the rightful owner of traditional knowledge, especially when that knowledge has been around for generations. Legal owners to traditional knowledge may be the individual, the community, the local/state/national government and even nongovernmental organizations that represent the indigenous people [20]. Furthermore, communities may be defined by geographic boundaries, ethnicity or political divide. The challenge of identifying ownership and benefit recipients due to such ambiguity can lead to major legal complications in negotiations involving know-how licenses (discussed in the previous segment) and in the identification of local authority to provide PIC (discussed at the end of this essay).

IV. Negotiations and Forms of Agreement Structure

In the ICBG, program leaders of the cooperative groups generally lay out the basic principles of the agreements, which are then reviewed by associate programs within each group. Since scientists, conservation workers or government representatives often do not have the legal competence or experience to evaluate terms of agreements (unlike industrial partners), they are highly encouraged to utilize legal counsel to analyze the potential pitfalls and provide advice on the draft agreement early on, prior to the commencement of the research project. Given that all circumstances cannot be anticipated in advance, negotiations may continue throughout the progress of the project and agreements may be modified accordingly. Negotiated issues include ownership and conditions of material transfer, patent rights, types of benefits and benefit recipients. As part of an agreement, full disclosure of research objectives and PIC from source-country participants is also emphasized and these often require clear communication and intense negotiations.

Various forms of Agreement Structure have been encountered in various ICBGs. At the primary level each ICBG begins with a cooperative agreement between the U.S. Government (USG) and the principal investigator or program leader of the ICBG at a U.S. university. Funding from the USG is contingent upon the fulfillment of ICBG principles and satisfactory progress on the part of the groups as well as availability of funds in the USG. Agreements have been drawn on the basis of simple “one-contract” model or highly complex “wheel-of-contracts” model and everything in between. In the one-contract model, all participating associate programs have a single multilateral contract agreement with the lead investigator, who in turn has a legal agreement with the USG. While this is the simplest of all agreement structures, it is the most difficult and time-consuming to negotiate, as all parties need to come to agreement on all terms as partners. In the wheel-of-contracts model, which represents an extreme scenario, participating associate programs have bilateral agreements with each other and with the lead program. Such bilateral agreements are simpler to negotiate and do not affect the entire group all at once. However, this structure requires efficient management on part of the lead program that acts as the “hub.” A third model is the “dual-contract model” in which the collections and benefit-sharing agreement is separate from the commercial research and development agreement and participating associate programs may be signatories to either one or the other or both, hence exhibiting an overlapping structure. This arrangement helps to separate the aspects of resource and knowledge utilization, which are culturally and politically sensitive issues, from the aspects of commercial research and development.

All the salient points discussed above have been encountered in at least one or more ICBGs.

We end this discussion by providing three examples of R&D cooperation for drug development from Natural Products.

2. Macrocyclic Drugs

Although the structural complexity and synthetic intractability limit their pharmaceutical application, macrocycles have broad applications in drug discovery and development; and numerous natural macrocyclic compounds present exceptional therapeutic potential and unrivalled biological activities [1]. Historically, macrocyclic molecules represent a successfully documented drug class in the clinic. In this section we review clinically used macrocyclic drugs and mainly focus on their structural aspect, mechanism of action and primary clinical indication. Notably, the macrocyclic antibiotics (Figure 1 , Figure 2) constitute one of the most successful classes of macrocyclic drugs in clinical practice. Among them, vancomycin is a macrocyclic glycopeptide antibiotics for the treatment of Gram-positive bacterial infections, such as methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-resistant Streptococcus pneumonia [9,10]. Chemically, vancomycin is a hydrophilic glycopeptide containing a glycosylated hexapeptide chain and aromatic rings cross linked by aryl ether bonds into a rigid molecular framework. It is not orally bioavailable due to poor absorption in the gastrointestinal tract, however, it can be used as an oral antibiotic for the treatment of C. difficile-associated diarrhea and enterocolitis caused by Staphylococcus aureus [9,10]. In 2009, its synthetic lipoglycopeptide derivative telavancin was approved by the U.S. FDA for the treatment of complicated skin and skin structure infections (cSSSIs) caused by MSSA, MRSA, and vancomycin-susceptible Enterococcus faecalis, and Streptococcus pyogenes, Streptococcus agalactiae, or Streptococcus anginosus group [10,11,12]. Mechanistically, this glycopeptide class inhibits the peptidoglycan biosynthesis of bacterial cell wall by binding tightly to D-alanyl-D-alanine portion of cell wall precursor, as well as disrupts cell membrane integrity [10,13,14].

Figure 1. Clinically used macrocyclic antibiotics.

Figure 1. Clinically used macrocyclic antibiotics.

Figure 2. Additional macrocyclic antibiotics.

Figure 2. Additional macrocyclic antibiotics.

In addition, daptomycin is a new cyclic lipopeptide antibiotic produced from Streptomyces roseosporus [15]. It was approved by the U.S. FDA in 2003 for the treatment of cSSSIs caused by susceptible aerobic Gram-positive organisms and S. aureus bacteremia caused by MSSA or MRSA [10,16]. Daptomycin rapidly depolarizes bacterial membrane by binding to components of the cell membrane of susceptible organisms and inhibits macromolecular biosynthesis of DNA, RNA, and protein [10,17]. Fidaxomicin, obtained from the fermentation broth of Dactylosporangium aurantiacum subspecies hamdenesis, represents the first in a new macrocyclic class of narrow spectrum antibiotics [18,19,20]. It was approved by the U.S. FDA for the treatment of C. difficile-associated diarrhea in 2011 [10]. Bacitracin A, generated from the licheniformis group of Bacillus subtilis, is a branched cyclic polypeptide broad spectrum antibiotic targeting both Gram-positive and -negative organisms [21,22]. It works by inhibiting the late stage peptidoglycan biosynthesis and disrupting plasma membrane function [23]. Polymyxins A-E belong to an old class of cationic cyclic polypeptide antibiotics that consist of a cyclic positively charged decapeptide with an either 6-methyl-octanic acid or 6-methyleptanoic acid fatty acid side chain. Only polymyxins B and E in this class are used in the clinic, which are primarily used for the treatment of Gram-negative bacterial infections such as Acinetobacter species, Pseudomonas aeruginosa, Klebsiella species, and Enterobacter species [10,24,25,26]. Polymyxin B disrupts bacterial membrane integrity by binding to phospholipids in cytoplasmic membranes [10,25].

The prototype macrolide antibiotic erythromycin, bearing a 14-membered macrocyclic lactone motif, was isolated from the fermentation broth of the fungus Saccharopolyspora erythraea and used for the treatment of susceptible bacterial infections [27,28]. Clarithromycin, a semisynthetic derivative of erythromycin with a 6-methoxyl ether functionality and improved acidic stability, is an effective macrolide antibiotic for the treatment of chronic bronchitis and erysipelas [29,30]. Azithromycin, a 15-membered expanded ring derivative of erythromycin, is another advanced and effective antibacterial agent in this macrolide class [29,30]. Telithromycin, the first ketolide antibiotic bearing a 14-membered lactone ring and an interesting alkyl-aryl side chain linked with a cyclic carbamate moiety, was approved by the U.S. FDA in 2004 and is used for the treatment of mild-to-moderate community-acquired pneumonia [10,30,31]. This class of macrolide antibiotics exerts its antibacterial action by binding to the 50S subunit of the bacterial ribosome resulting in the inhibition of RNA-dependent protein synthesis [10,32]. Spiramycin is another glycomacrolide antibiotic which is currently not available in the U.S.. It inhibits bacterial growth of susceptible organisms with unknown mechanism of action; and is used for the treatment of bacterial infections of the respiratory tract, buccal cavity, skin and soft tissues due to susceptible organisms [10,33].

As shown in Figure 2, the streptogramin family represents another important class of naturally occurring macrocyclic antibiotics, which includes streptogramin A, streptogramin B, quinupristin, and dalfopristin [34]. This chemical class functions as bacterial protein synthesis inhibitors [34]. Structurally, the streptogramin group A has a 23-membered unsaturated macrolactone with peptide bonds, while the streptogramin group B belongs to a cyclic hexadepsipeptide class. The combination of quinupristin and dalfopristin is used synergistically for the treatment of cSSSIs caused by MSSA or Streptococcus pyogenes [10,35].

Rifamycin and its derivatives constitute another notable class of antibacterial agents. The rifamycin antibiotic family includes rifampin, rifapentine, rifabutin, and rifaximin. Chemically, this class consists of a 25-membered macrolactam ring bearing a naphthalenic aromatic moiety connected to an aliphatic chain. Mechanistically, this antibacterial class inhibits bacterial RNA synthesis by binding to the β-subunit of DNA-dependent RNA polymerase [36] and it is primarily used for the treatment of tuberculosis except that rifaximin is clinically used for the treatment of traveler’s diarrhea caused by noninvasive strains of E. coli [10]. In addition, capreomycin (administered as a mixture of capreomycin 1A and 1B) is a strongly basic and cyclic polypeptide antibiotic, which is used in the second line TB regimens for the treatment of multi-drug resistant tuberculosis (MDR-TB) in conjunction with other antibiotics [10,37].

Macrocyclic antifungal agents are illustrated in Figure 3. Nystatin, amphotericin B, and natamycin belong to a chemical class of polyene antifungal drugs, which structurally consists of a macrocyclic lactone scaffold; a hydrophilic region containing multiple OH groups, a COOH functionality, and an aminosugar moiety; and a hydrophobic region containing a chromophore of the 4–7 conjugated double bond system. This naturally occurring antifungal class works by binding to ergosterol in fungal cell membrane and thus disrupting fungal membrane function [38,39]. Nystatin, the first clinically used agent in this polyene class, displays potent activity for invasive Candida infection; however, it can only be used topically due to its severe toxicity for systemic use [10]. In contrast, amphotericin B is used parenterally for the treatment of severe systemic and CNS fungal infections caused by susceptible fungi [10]. Natamycin is the only topical ophthalmic antifungal agent approved by the U.S. FDA for the treatment of blepharitis, conjunctivitis, and keratitis caused by susceptible fungi (Aspergillus, Candida, Cephalosporium, Fusarium, and Penicillium) [10].

Figure 3. Clinically used macrocyclic antifungal and antiparasitic agents.

Figure 3. Clinically used macrocyclic antifungal and antiparasitic agents.

Structurally, antifungal echinocandins belong to a lipopeptide chemical class, which includes a large cyclic hexapeptide linked to a long fatty acid tail or lipophilic side chain. The echinocandin family includes anidulafungin, caspofungin, and micafungin and is used parenterally for the treatment of candidemia, other forms of Candida infections, and invasive Aspergillus infections [10,40,41,42]. This drug class demonstrates antifungal activity by inhibiting 1,3-β-D-glucan synthase, an important target in the fungal cell wall biosynthesis [39,40].

On the other hand, macrocycles have also been used as antiparasitic agents. One such example, ivermectin, bearing a 16-membered macrocyclic ring, is an effective antiparasitic and anthelmintic agent for the treatment of strongyloidiasis of the intestinal tract and onchocerciasis, as well as the topical treatment of head lice (Figure 3) [10,43,44]. Ivermectin binds to glutamate-gated chloride ion channels with high selectivity and strong affinity in invertebrate nerve and muscle cells, which ultimately leads to the death of the parasite due to increased permeability of cell membranes to chloride ions and subsequent hyperpolarization of the nerve or muscle cell [10,43].

Macrocyclic anticancer chemotherapeutic agents are shown in Figure 4. As one of the older chemotherapy drugs, dactinomycin, isolated from soil bacteria of the genus Streptomyces, is a cyclic polypeptide intravenous antibiotic with anticancer activity [45]. It binds to DNA and causes subsequent inhibition of RNA synthesis and is used in the treatment of Wilm’s tumor, gestational trophoblastic neoplasia and rhabdomyosarcoma [10]. Epothilone B, a 16-membered polyketide macrolactone with a methylthiazole side chain, exerts its cytotoxic effects through promoting microtubule assembly, interfering with the late G2 mitotic phase, and inhibiting cell replication [10]. It has similar mechanistic profile as taxanes but improved solubility and milder side effect and become a new class of anticancer drugs for the treatment of metastatic or locally-advanced breast cancer (refractory or resistant) [10,46]. The semisynthetic macrolactam analogue ixabepilone of epothilone B is used for the treatment of advanced breast cancer [47]. In addition, romidepsin, a histone deacetylase (HDAC) inhibitor generated from the bacteria Chromobacterium violaceum, is an antineoplastic prodrug for the treatment of refractory cutaneous T-cell lymphoma and refractory peripheral T-cell lymphoma [10,48].

Figure 4. Macrocycles used as cancer chemotherapeutic and immunosuppressant agents.

Figure 4. Macrocycles used as cancer chemotherapeutic and immunosuppressant agents.

Macrocycles have also been clinically used as immunosuppressant agents, one such example, the cyclic polypeptide cyclosporine inhibits the production and release of interleukin-2 (IL-2), inhibits IL-2-induced activation of resting T-lymphocytes and thus inhibits T cell-mediated immune responses [10,49]. It is frequently used to prevent rejection in organ transplant recipients [10]. Another macrolide lactone class of immunosuppressive agents includes sirolimus (rapamycin) [50

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